Imidazole derivatives as adenosine deaminase inhibitors

ABSTRACT

Imidazole compounds having adenosine deaminase inhibitory activity represented by the formula (I) wherein R1 is aryl or heterocyclic group which is optionally substituted with substituent(s); R 2  is lower alkyl; R 3  is hydroxy or protected hydroxy; -A- is lower alkylene; and —X— is —O— or —S—; provided that when then R 1  is aryl which is substituted with substituent(s), or heterocyclic group which is optionally substituted with substituent(s), its prodrug, or their salt. The compounds are useful for treating and/or preventing diseases for which adenosine is effective.

TECHNICAL FIELD

This invention relates to novel imidazole compounds havingpharmacological activity, to a process for their production and to apharmaceutical composition containing the same.

BACKGROUND ART

Adenosine (Ado) is an endogenous purine nucleoside released by cells aspart of the normal metabolic machinery. Ado has wide variety ofbiological activities, namely potent antiinflammatory andimmunosuppressive properties, protective effects in cardiovascular andcerebrovascular ischemia, anticonvulsant effects and modulation effectsof platelet aggregation, lipolysis, glycogenesis, blood flow andneurotransmission. Ado shows the biological activities by binding to itsreceptors anchored in the cell membrane. Therefore, it is the beneficialtreatment for many diseases to perform the pharmacological elevation ofextracellular Ado concentrations.

Adenosine deaminase (ADA) catalyzes an essentially irreversibledeamination of adenosine and deoxyadenosine to inosine and deoxyinosine,respectively. In the last 10 years, ADA, which was considered to becytosolic, has been found on the cell surface of many cells. Thus,blocking ADA activity with specific inhibitor is the potent way toelevate Ado concentrations in biological systems and the beneficialtreatment for many diseases.

Some compounds have been known to have inhibitory activity of ADA (J.Med. Chem. 27, 274–278, 1984; ibid. 31, 390–393, 1988; ibid. 34,1187–1192, 1991; ibid. 35, 4180–4184, 1992; ibid. 37, 305–308, 1994;ibid. 37, 3844–3849, 1994; WO98/02166).

Known imidazole compounds with pharmaceutical activity other than ADAinhibitory activity are described in U.S. Pat. No. 4,451,478 andWO97/26883.

Furthermore, some imidazole derivatives having ADA inhibitory activityhave been reported, for example, as described in Drug DevelopementResearch 28, 253–258, 1993.

DISCLOSURE OF THE INVENTION

This invention relates to novel imidazole compounds, which havepharmaceutical activity such as ADA inhibiting activity, to a processfor their production, to a pharmaceutical composition containing thesame, and to a use thereof.

One object of this invention is to provide the novel imidazolecompounds, which have an ADA inhibiting activity.

Another object of this invention is to provide a process for productionof the imidazole compounds.

A further object of this invention is to provide a pharmaceuticalcomposition containing the imidazole compound as an active ingredient.

Still further object of this invention is to provide a use of theimidazole compound for manufacturing a medicament for treating orpreventing various diseases, or a method of treating or preventingvarious diseases by administering the imidazole compound in an effectiveamount to elevate adenosine concentration.

The imidazole compound of this invention can be represented by thefollowing formula (I):

wherein R¹ is aryl or heterocyclic group which is optionally substitutedwith substituent(s);

R² is lower alkyl;

R³ is hydroxy or protected hydroxy;

-A- is lower alkylene; and

—X— is —O— or —S—;

provided that when —X— is —O—, then R¹ is aryl which is substituted withsubstituent(s), or heterocyclic group which is optionally substitutedwith substituent(s), its prodrug, or their salt.

In the compound of formula (I), R¹ is preferably (1) aryl optionallysubstituted with substituent(s) selected from the group consisting oflower alkyl, halogen, optionally substituted aryl, optionallysubstituted heterocyclic group, lower alkoxy, and cyano, (2) condensedheterocyclic group optionally substituted with suitable substituent(s)selected from the group consisting of lower alkyl, optionallysubstituted aryl, and aryl(lower)alkyl, or (3) unsaturatedheteromonocyclic group containing 1 to 4 nitrogen atoms which isoptionally substituted with optionally substituted aryl. -A- ispreferably methylene or ethylene. R² is preferably methyl.

The compound (I), its prodrug, or their salt can be prepared by thefollowing processes. In the following formulae, compounds may beprodrugs or their salts.

Process 1

The compound (I) wherein —X— is —O—, and R³ is not hydroxy can beobtained by reacting a compound of formula (II)R¹—OH  (II)wherein R¹ is as defined above, with a compound of formula (III)

wherein R², R³, and -A- are as defined above, and X¹ is hydroxy or aleaving group (such as halogen, alkanesulfonyloxy, arylsulfonyloxy, andthe like), provided that R³ is not hydroxy.

The reaction may be carried out in a manner such as the Mitsunobureaction or the modification thereof. This reaction can be preferablycarried out in the presence of di(lower)alkyl azodicarboxylate (e.g.,diethyl azodicarboxylate, etc.) and trialkyl or triarylphosphines (e.g.,triphenylphosphine, etc.) in a solvent, which does not adversely affectthe reaction, such as tetrahydrofuran, diethyl ether, or the like. Thereaction temperature is not critical and the reaction is usually carriedout under cooling to warming.

Alternatively, in the case where X¹ is a leaving group, the compound (I)can also be produced by reacting the compound (III) with the compound(II) in the presence of a base such as sodium hydride, potassiumtert-butoxide, or potassium carbonate in a solvent such asN,N-dimethylformamide (DMF) from room temperature to 100° C.

Process 2

The compound (I) wherein —X— is —O—, and R³ is hydroxy can be obtainedby reacting a compound of formula (I-1)

wherein R¹, R², and -A- are as defined above, and R′ is hydroxyprotective group, with a deprotecting agent.

The compound (I-1) can be reacted with a deprotecting agent such aspalladium hydroxide on carbon/cyclohexene, trimethylsilyl iodide, ortetra-n-butylammonium fluoride in a solvent, which does not adverselyaffect the reaction, such as ethanol, chloroform, or tetrahydrofuran.The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

Process 3

The compound (I) can be obtained by reacting a compound of formula (IV)

wherein R¹, R², R³, -A-, and —X— are as defined above, with aqueousammonia solution.

The reaction can be carried out in a solvent, which does not adverselyaffect the reaction, such as methanol, 1,2-dimethoxyethane, or the likefrom 50° C. to 120° C.

In the following, suitable examples of the definitions to be includedwithin the scope of the invention are explained in detail.

The term “lower” means a group having 1 to 6 carbon atom(s), unlessotherwise provided.

Suitable “lower alkyl” and lower alkyl moiety of “lower alkoxy”,“halo(lower)alkyl,” and “aryl(lower)alkyl” include a straight orbranched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, hexyl, or the like, with methyl, ethyl, andtert-butyl being preferred.

Suitable “lower alkylene” may be straight or branched one having 1 to 8carbon atom(s), such as methylene, ethylene, trimethylene,tetramethylene, pentametylene, hexamethylene, or the like, withmethylene and ethylene being preferred.

Suitable “halogen” and halogen moiety of “halo(lower)alkyl” includefluorine, chlorine, bromine, or iodine.

Suitable “aryl” and aryl moiety of “aryl(lower)alkyl” include phenyl,naphthyl, tolyl, xylyl, fluorenyl, or the like, with phenyl, naphthyl,and fluorenyl being preferred.

Suitable “heterocyclic group” includes one containing at least oneheteroatom selected from the group consisting of nitrogen, sulfur, andoxygen atoms, and include saturated or unsaturated, monocyclic orpolycyclic heterocyclic group such as:

(1) unsaturated, 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic group containing 1 to 4 nitrogen atoms, for example,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.], tetrazolyl [e.g.,1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.;

(2) saturated, 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic group containing 1 to 4 nitrogen atoms, for example,pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.;

(3) unsaturated, condensed heterocyclic group containing 1 to 5 nitrogenatoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl[e.g., tetrazolo[1,5-b]pyridazinyl, etc.], etc.;

(4) unsaturated, 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,furyl, etc.;

(5) unsaturated, 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms, for example,thienyl, etc.;

(6) unsaturated, 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g.,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.], etc.;

(7) saturated, 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms, for example, morpholinyl, etc.;

(8) unsaturated, condensed heterocyclic group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl,benzoxadiazolyl, etc.;

(9) unsaturated, 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.], etc.;

(10) saturated, 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, for example, thiazolidinyl, etc.;

(11) unsaturated, condensed heterocyclic group containing 1 to 2 sulfuratoms and 1 to 3 nitrogen atoms, for example, benzothiazolyl,benzothiadiazolyl, etc.;

(12) unsaturated, condensed heterocyclic group containing 1 to 2 sulfuratoms or 1 to 2 oxygen atoms, for example, benzo[b]thiophenyl,benzofuranyl, dibenzofuranyl, etc.; or the like.

Among the above, more preferable “heterocyclic group” is above-mentioned(1), (3) (5), (6), (7), (8), (9), (11), and (12), in which the mostpreferable one is pyrrolyl (e.g., 1-pyrrolyl, etc.), pyridyl (e.g.,2-pyridyl, 3-pyridyl, etc.), indolyl (e.g., 1H-indol-5-yl, etc.),benzimidazolyl (e.g., 1H-benzimidazol-2-yl, etc.), quinolyl (e.g.,2-quinolyl, 6-quinolyl, etc.), isoquinolyl (e.g., 3-isoquinolyl,7-isoquinolyl, etc.), thienyl (e.g., 2-thienyl, etc.), morpholinyl(e.g., 4-morpholinyl, etc.), benzoxazolyl (e.g., 2-benzoxazolyl,6-benzoxazolyl, etc.), thiazolyl (e.g., 4-thiazolyl, etc.),benzothiazolyl (e.g., 5-benzothiazolyl, etc.), benzo[b]thiophenyl (e.g.,2-benzo[b]thiophenyl, etc.), benzofuranyl (e.g., 2-benzofuranyl, etc.),or dibenzofuranyl (e.g., 2-dibenzofuranyl, etc.).

Suitable “protected hydroxy” includes lower alkoxy optionallysubstituted with aryl (e.g., benzyloxy, etc.); acyloxy; ortri(lower)alkylsilyloxy (i.e., trimethylsilyloxy,tert-butyldimethylsilyloxy, etc.); or the like.

Suitable hydroxy protective groups in the protected hydroxy groupinclude lower alkyl optionally substituted with aryl; acyl;tri(lower)alkylsilyl (i.e., trimethylsilyl, tert-butyldimethyl-silyl,etc.); or the like. Here, suitable “acyl” includes acetyl,trifluoroacetyl, or the like.

Suitable “leaving group” includes halogen, acyloxy (e.g., acetyloxy,trifluoroacetyloxy, etc.), lower alkylsulfonyloxy (e.g.,methanesulfonyloxy, etc.), triarylphosphinoxy (e.g., —O—P⁺(C₆H₅)₃,etc.), or the like.

Suitable substituent(s) of “optionally substituted aryl” and “optionallysubstituted heterocyclic group” include lower alkyl, halo(lower)alkyl,lower alkoxy, halogen, aryl, aryl(lower)alkyl, cyano, or the like.

The term “optionally substituted aryl” means aryl which is optionallysubstituted with one or more substituent(s) selected from the groupconsisting of lower alkyl, halo(lower)alkyl, lower alkoxy, halogen,cyano, and the like.

Examples of the “optionally substituted aryl” include unsubstituted arylsuch as phenyl or the like; haloaryl such as 4-fluorophenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,5-dichlorophenyl, orthe like; lower alkylaryl such as 4-methylphenyl, or the like; loweralkoxyaryl such as 3-methoxyphenyl, 4-methoxyphenyl, or the like;halo(lower)alkylaryl such as 4-(trifluoromethyl)phenyl or the like;cyanoaryl such as 4-cyanophenyl, or the like; etc.

The term “optionally substituted heterocyclic group” means heterocyclicgroup which is optionally substituted with one or more substituent(s)selected from the group consisting of lower alkyl, lower alkoxy,halogen, aryl, aryl(lower)alkyl, and the like.

Examples of the “optionally substituted heterocyclic group” includeunsubstituted heterocyclic group such as 1H-benzimidazol-2-yl,2-thienyl, 4-morpholinyl, 2-benzoxazolyl, 1-benzothien-2-yl,2-benzofuranyl, 1H-pyrrol-1-yl, or the like; heterocyclic groupsubstituted with lower alkyl, such as 5-methyl-2-thienyl or the like;heterocyclic group substituted with lower alkoxy, such as6-methoxy-3-pyridyl or the like; heterocyclic group substituted withhalogen, such as 5-chloro-2-thienyl, 6-chloro-3-pyridyl, or the like;heterocyclic group substituted with aryl, such as 2-phenylthiazol-4-ylor the like; heterocyclic group substituted with aryl(lower)alkyl, suchas 2-benzylthiazol-4-yl or the like.

Suitable salts of the compounds of the present invention arepharmaceutically acceptable conventional non-toxic salts and can be anorganic acid addition salt (e.g., formate, acetate, trifluoroacetate,maleate, tartarate, oxalate, methanesulfonate, benzenesulfonate,toluenesulfonate, etc.), an inorganic acid addition salt (e.g.,hydrochloride, hydrobromide, sulfate, phosphate, etc.), a salt with anamino acid (e.g., aspartic acid salt, glutamic acid salt, etc.), or thelike.

The “prodrug” means the derivatives of compounds of the presentinvention having a chemically or metabolically degradable group, whichbecomes pharmaceutically active after biotransformation.

The compounds of formula (I) may contain one or more asymmetric centersand thus they can exist as enantiomers or diastereoisomers. Furthermorecertain compounds of formula (I) which contain alkenyl groups may existas cis- or trans-isomers. In each instance, the invention includes bothmixtures and separate individual isomers.

The compounds of the formula (I) may also exist in tautomeric forms andthe invention includes both mixtures and separate individual tautomers.

The compound of the formula (I) and its salt can be in a form of asolvate, which is included within the scope of the present invention.The solvate preferably include a hydrate and an ethanolate.

Also included in the scope of invention are radiolabelled derivatives ofcompounds of formula (I) which are suitable for biological studies.

The compound of the present invention can be purified by anyconventional purification methods employed for purifying organiccompounds, such as recrystallization, column chromatography, thin-layerchromatography, high-performance liquid chromatography, and the like.The compounds can be identified by conventional methods such as NMRspectrometry, mass spectrometry, IR spectrometry, elemental analysis,measurement of melting point, and the like.

The compound (I), its prodrug, or their salt can be administered aloneor in the form of a mixture, preferably, with a pharmaceutical vehicleor carrier.

The active ingredient of this invention can be used in the form of apharmaceutical preparation, for example, in solid, semisolid, or liquidform, which contains a compound (I), as an active ingredient, inadmixture with an organic or inorganic carrier or excipient suitable fororal, external (topical), enteral, intravenous, intramuscular,parenteral, or intramucous applications. The active ingredient can beformulated, for example, with the conventional non-toxic,pharmaceutically acceptable carriers for ointment, cream, plaster,tablets, pellets, capsules, suppositories, solution (saline, forexample), emulsion, suspension (olive oil, for example), aerosols,pills, powders, syrups, injections, troches, cataplasms, aromaticwaters, lotions, buccal tablets, sublingual tablets, nasal drops, andany other form suitable for use. The carriers which can be used arewater, wax, glucose, lactose, gum acacia, gelatin, mannitol, starchpaster, magnesium trisilicate, talc, corn starch, keratin, paraffin,colloidal silica, potato starch, urea, and other carriers suitable foruse in manufacturing preparations, in solid, semisolid, or liquid form,and in addition, auxiliary, stabilizing, thickening, and coloring agentsand perfumes may be used. The active compound is included in apharmaceutical composition in an effective amount sufficient to producethe desired effect upon the process or condition of the diseases.

The active ingredient can be formulated into, for example, preparationsfor oral application, preparations for injection, preparations forexternal application, preparations for inhalation, preparations forapplication to mucous membranes, etc.

Mammals which may be treated by the present invention include livestockmammals such as cows, horses, etc., domestic animals such as dogs, cats,rats, etc., and humans, and preferably humans.

While the dosage of therapeutically effective amount of the compound (I)will vary depending upon the age and condition of each individualpatient, an average single dose to a human patient of about 0.01 mg, 0.1mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg, and 1000 mg of thecompound (I) may be effective for treating the above-mentioned diseases.In general, amounts between 0.01 mg/body and about 1,000 mg/body may beadministered per day.

An ADA inhibitor, such as the compound (I) or its pharmaceuticallyacceptable salts of this invention, possesses ADA inhibiting activityand are thus useful in immunomodulation, especially immunosuppression,antiinflammation and treatment and prevention of various diseases forwhich Ado is effective. Examples of the diseases are as follows:

-   a) Autoimmune diseases and inflammatory conditions, e.g., various    pains collagen diseases, autoimmune diseases, various immunity    diseases, and the like in human beings or animals, and more    particularly for the treating and/or preventing inflammation and    pain in joint and muscle (e.g., rheumatoid arthritis, rheumatoid    spondylitis, osteoarthritis, gouty arthritis, etc.), inflammatory    skin condition (e.g., sunburn, eczema, etc.), inflammatory eye    condition (e.g., conjunctivitis, etc.), lung disorder in which    inflammation is involved (e.g., asthma, bronchitis, pigeon fancier's    disease, farmer's lung, etc.), condition of the gastrointestinal    tract associated with inflammation (e.g., aphthous ulcer, Crohn's    disease, atrophic gastritis, ulcerative colitis, coeliac disease,    regional ileitis, irritable bowel syndrome, etc.), gingivitis,    (inflammation, pain and tumescence after operation or injury),    pyrexia, pain and other conditions associated with inflammation,    systemic lupus erythematosus, scleroderma, polymyositis,    polychondritis, periarteritis nodosa, ankylosing spondylitis,    inflammatory chronic renal condition (e.g., nephrotic syndrome,    glomerulonephritis, membranous nephritis, etc.), acute nephritis,    rheumatic fever, Sjogren's syndrome, Behcet disease, thyroiditis,    type I diabetes, dermatomyositis, chronic active hepatitis, acute    hepatitis, myasthenia gravis, idiopathic sprue, Grave's disease,    multiple sclerosis, primary billiary cirrhoris, Reiter's syndrome,    autoimmune hematological disorders (e.g., hemolytic anemia, pure red    cell anemia, idiopathic thrombocytopenia; aplastic anemia, etc.),    myasthenia gravis, uveitis, contact dermatitis, psoriasis, Kawasaki    disease, sarcoidosis, Wegner's granulomatosis, Hodgkin's disease, or    the like;-   b) Organ or tissue allo- or xeno-transplant rejection, e.g., kidney,    liver, heart, lung, combined heart-lung, bone marrow, islet cells,    pancreatic, skin, chromaffin or dopamine producing cells, small    bowel, or corneal transplantation. Treating and/or preventing    graft-versus-host disease, such as occurs following bone marrow    transplantation;-   c) Chronic pain (e.g., cancer pain, diabetic neuropathy, etc);-   d) Various leukemias, including virus induced or various induced    lymphomas; and-   e) Diseases that arise from, or are aggravated by, insufficient    blood flow through a particular organ or portion thereof, e.g.,    heart attacks or strokes, the microvascular disease of diabetes    mellitus, atherosclerosis, or events resulting in a less prolonged    loss of blood flow (e.g., angina pectoris, transient ischemic    attacks, bowel ischemia, kidney ischemia, intermittant claudication    of skeletal muscle, migraine headaches, Raynaud's phenomenon), or    the like.

An ADA inhibitor, such as the compound (I) or its pharmaceuticallyacceptable salt of this invention, is useful for protection against theprogression of glomerulosclerosis by suppressing glomerular hypertensionand hyperfiltration, and thus useful for treatment and/or prevention ofglomerulosclerosis.

An ADA inhibitor, such as the compound (I) or its pharmaceuticallyacceptable salt of this invention, is useful for complementing thedefect of an IL-2 inhibitor, such as FK506, cyclosporin, or the like, inimmunosuppresive effects. Thus, the combination use of the two compoundsenables treatment and prevention of various diseases and conditions inneed of immunosuppression.

Any patents, patent applications, and publications cited herein areincorporated by reference.

In order to illustrate the usefulness of the object compound (I), thepharmacological test data of the compound (I) are shown in thefollowing.

Adenosine Deaminase (ADA) Enzyme Assay

Test Compound:

-   -   1-[(2S,3R)-5-(1,1′-biphenyl-3-yloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide        (Example 20)    -   1-{(2S,3R)-2-hydroxy-5-[3-(2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide        (Example 32)    -   1-[(2S,3R)-2-hydroxy-5-(2-quinolyloxy)-3-pentyl]imidazole-4-carboxamide        (Example 49)    -   1-[(2S,3R)-2-hydroxy-5-(2-naphthylthio)-3-pentyl]imidazole-4-carboxamide        (Example 76)    -   1-[(2S,3R)-2-hydroxy-5-(2-quinolylthio)-3-pentyl]imidazole-4-carboxamide        (Example 78)        Test Method:

The reaction velocity (V) is measured by a change in absorbance at 265nm (A265) resulting from the deamination of adenosine. Human ADA wasexpressed and purified from ADA-deficient bacterial strain. Reactionmixtures of a total volume of 200 μl contained 0.16 μg/ml of ADA and 0.1mM of adenosine and test compound in 10 mM phosphate buffer saline (pH7.4). The reaction was started by addition of ADA to a mixture ofadenosine and test compound. The reaction was followed at roomtemperature by recording decrease in A265 for 3 minutes in SPECTRAmax250 (Molecular Devices, USA) to automatically calculate V_(max).Inhibitory potency of test compound was expressed as IC₅₀ value, thedrug concentration required to produce 50% inhibition of V_(max) incomparison to vehicle treatment.

Results: Test Compound IC₅₀ (nM) Example 20 <20 Example 32 <20 Example49 <20 Example 76 <20 Example 78 <20

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows chemical formulae of compound (1) to compound (8).

FIG. 2 shows chemical formulae of compound (9) to compound (16).

FIG. 3 shows chemical formulae of compound (17) to compound (24).

FIG. 4 shows chemical formulae of compound (25) to compound (32).

FIG. 5 shows chemical formulae of compound (33) to compound (40).

FIG. 6 shows chemical formulae of compound (41) to compound (48).

FIG. 7 shows chemical formulae of compound (49) to compound (56).

FIG. 8 shows chemical formulae of compound (57) to compound (64).

FIG. 9 shows chemical formulae of compound (65) to compound (72).

FIG. 10 shows chemical formulae of compound (73) to compound (80).

FIG. 11 shows chemical formulae of compound (81) to compound (88).

FIG. 12 shows chemical formulae of compound (89) to compound (96).

FIG. 13 shows chemical formulae of compound (97) to compound (104).

BEST MODE FOR CARRYING OUT THE INVENTION

The following Preparation and Examples are given for the purpose ofillustrating the present invention in detail, but are not to beconstrued to limit the scope of the present invention.

EXAMPLE 1

Under N₂, to a solution of 6-hydroxyquinoline (43 mg, 0.296 mmol) in DMF(3 ml) was added potassium carbonate (82 mg, 0.593 mmol) at roomtemperature. The reaction mixture was stirred for 30 minutes.1-[(2S,3R)-2-benzyloxy-5-methanesulfonyloxy-3-pentyl]imidazole-4-carboxamidewas added and the resulting mixture was stirred for 6 h at 70° C. Thereaction mixture was poured into water (30 ml) and extracted with ethylacetate. The organic layer was washed with brine, dried (sodium sulfate)and evaporated in vacuo. The residue was purified by silica gel (8 g)chromatography eluting with chloroform/methanol (100:1 to 30:1) to give1-[(2S,3R)-2-benzyloxy-5-(6-quinolyloxy)-3-pentyl]imidazole-4-carboxamide(1) (62.5 mg, 48.9%).

IR (KBr, cm⁻¹): 3600–2800, 1664, 1597, 1230, 1110

NMR (CDCl₃, δ): 1.21 (3H, d, J=6 Hz), 2.15–2.75 (2H, m), 3.60–4.20 (3H,m), 4.30–4.50 (2H, m), 4.67 (1H, d, J=12 Hz), 5.36 (1H, brs), 6.91 (1H,d, J=3 Hz), 6.92 (1H, brs), 7.20–7.40 (7H, m), 7.46 (1H, s), 7.70 (1H,s), 7.99 (2H, d, J=9 Hz), 8.77 (1H, dd, J=4.2 Hz)

MS: 431 (M+H)⁺

[α]_(D) ^(22.5)=+63.50° (C=0.50, EtOH)

EXAMPLE 2

To a solution of1-[(2S,3R)-2-benzyloxy-5-(6-quinolyloxy)-3-pentyl]imidazole-4-carboxamide(58 mg, 0.135 mmol) in cyclohexene (2.5 ml) and ethanol (5 ml) was added20% palladium hydroxide on carbon (50 mg). The resulting mixture wasstirred at reflux for 8 h. After cooling to room temperature, themixture was filtered through Celite and washed with ethanol. Thefiltrate was concentrated in vacuo and then the residue was purified bysilica gel (1.5 g) chromatography eluted with chloroform/methanol (50:1to 10:1) to give1-[(2S,3R)-2-hydroxy-5-(6-quinolyloxy)-3-pentyl]imidazole-4-carboxamide(2) (39.8 mg, 86.8%).

IR (KBr, cm⁻¹): 3700–2800, 1664, 1595, 1232, 1120

NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.20–2.65 (2H, m), 3.65–4.40(4H, m), 5.21 (1H, d, J=5 Hz), 7.03 (1H, brs), 7.15–7.55 (4H, m), 7.72(1H, s), 7.78 (1H, s), 7.90 (1H, d, J=9 Hz), 8.19 (1H, d, J=8 Hz), 8.71(1H, dd, J=4.2 Hz)

MS: 341 (M+H)⁺

EXAMPLE 3

To a stirred mixture of 3,4-dichlorophenol (129 mg, 0.791 mmol),1-[(2S,3R)-2-benzyloxy-5-hydroxy-3-pentyl]imidazole-4-carboxamide (80mg, 0.264 mmol), and triphenylphosphine (90 mg, 0.343 mmol) intetrahydrofuran (5 ml) was added dropwise diethyl azodicarboxylate (59.7mg, 0.343 mmol) at ice-bath temperature. After the mixture was stirredfor 2 h at room temperature, the solvent was removed in vacuo. Theresidue was purified by silica gel (10 g) chromatography eluting withchloroform/methanol (100:1 to 30:1) to give a mixture (120.6 mg, 102%)of1-[(2S,3R)-2-benzyloxy-5-(3,4-dichlorophenoxy)-3-pentyl]imidazole-4-carboxamide(3) and by-products. This material was used without furtherpurification.

IR (KBr, cm⁻¹): 3600–2800, 1664, 1593, 1232, 1124

NMR (CDCl₃, δ): 1.17 (3H, d, J=6 Hz), 2.05–2.70 (2H, m), 3.40–4.00 (3H,m), 4.29 (1H, m), 4.42 (1H, d, J=12 Hz), 4.65 (1H, d, J=12 Hz), 5.39(1H, brs), 6.63 (1H, dd, J=9.3 Hz), 6.88 (1H, d, J=3 Hz), 6.92 (1H,brs), 7.10–7.50 (7H, m), 7.65 (1H, s)

MS: 448 (M+H)⁺ (³⁵Cl×2), 450 (M+H)⁺ (³⁵Cl−³⁷Cl), 452 (M+H)⁺ (³⁷Cl×2)

EXAMPLE 4

To an ice cooled solution of1-[(2S,3R)-2-benzyloxy-5-(3,4-dichlorophenyloxy)-3-pentyl]imidazole-4-carboxamide(59.5 mg, 0.133 mmol) in chloroform (5 ml) was added trimethylsilyliodide (34.5 mg, 0.173 mmol). After 3 minutes, the ice bath was removed,and then stirred at room temperature overnight. The reaction wasquenched by addition of methanol. This mixture was extracted with ethylacetate, and the extracts were washed with brine, dried (sodium sulfate)and evaporated in vacuo. The residue was purified by silica gel (2.5 g)chromatography eluting with chloroform/methanol (50:1 to 10:1) to give1-[(2S,3R)-5-(3,4-dichlorophenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide(4) (40.4 mg, 85.0%) as a white amorphous solid.

IR (KBr, cm⁻¹): 3600–2800, 1658, 1593, 1234, 1126

NMR (DMSO-d₆, δ): 0.91 (3H, d, J=6 Hz), 2.05–2.55 (2H, m), 3.50–4.25(4H, m), 5.18 (1H, d, J=5 Hz), 6.88 (1H, dd, J=9.3 Hz), 7.02 (1H, brs),7.15 (1H, d, J=3 Hz), 7.24 (1H, brs), 7.48 (1H, d, J=9 Hz), 7.69 (1H,s), 7.73 (1H, s)

MS: 358 (M+H)⁺ (³⁵Cl×2), 360 (M+H)⁺ (³⁵Cl−³⁷Cl), 362 (M+H)⁺ (³⁷Cl×2)

EXAMPLE 5

This compound was prepared by a similar procedure to that of Example 3.

-   1-[(2S,3R)-2-benzyloxy-5-(2-dibenzofuranyloxy)-3-pentyl]imidazole-4-carboxamide    (5).

NMR (CDCl₃, δ): 1.20 (3H, d, J=6 Hz), 2.10–2.70 (2H, m) 3.55–4.10 (3H,m), 4.30–4.50 (2H, m), 4.66 (1H, d, J=12 Hz), 5.36 (1H, brs), 6.93 (1H,brs), 6.94 (1H, dd, J=9.3 Hz), 7.15–7.60 (11H, m), 7.71 (1H, s), 7.83(2H, d, J=8 Hz)

MS: 470 (M+H)+

EXAMPLE 6

This compound was prepared by a similar procedure to that of Example 2.

-   1-[(2S,3R)-5-(2-dibenzofuranyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide    (6).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1593, 1234, 1174

NMR (DMSO-d₆, δ): 1.00 (3H, d, J=6 Hz), 2.20–2.65 (2H, m) 3.60–4.50 (4H,m), 5.30 (1H, br), 7.01 (1H, dd, J=9.3 Hz), 7.25–7.80 (7H, m), 8.00 (1H,s), 8.09 (1H, d, J=8 Hz), 8.31 (1H, brs)

MS: 380 (M+H)⁺

EXAMPLE 7

This compound was prepared by a similar procedure to that of Example 3.

-   1-[(2S,3R)-2-benzyloxy-5-(2-methyl-5-benzothiazolyloxy)-3-pentyl]imidazole-4-carboxamide    (7).

NMR (CDCl₃, δ): 1.18 (3H, d, J=6 Hz), 2.10–2.75 (2H, m), 2.80 (3H, s),3.55–4.10 (3H, m), 4.30–4.50 (2H, m), 4.65 (1H, d, J=12 Hz), 5.34 (1H,brs), 6.88 (1H, dd, J=9.2 Hz), 6.91 (1H, brs), 7.10–7.40 (6H, m), 7.45(1H, s), 7.64 (1H, d, J=9 Hz), 7.67 (1H, s)

MS: 448 (M+H)⁺ (³⁵Cl×2), 450 (M+H)⁺ (³⁵Cl−³⁷Cl), 452 (M+H)⁺ (³⁷Cl×2)

EXAMPLE 8

This compound was prepared by a similar procedure to that of Example 2.

-   1-[(2S,3R)-2-hydroxy-5-(2-methyl-5-benzothiazolyloxy)-3-pentyl]imidazole-4-carboxamide    (8).

IR (KBr, cm⁻¹): 3700–2800, 1658, 1604, 1454, 1323, 1167, 1082, 1022

NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10–2.60 (2H, m), 2.75 (3H, s),3.55–4.30 (4H, m), 5.18 (1H, d, J=5 Hz) 6.96 (1H, dd, J=9.2 Hz), 7.02(1H, brs), 7.24 (1H, brs), 7.36 (1H, d, J=2 Hz), 7.70 (1H, s), 7.75 (1H,s), 7.85 (1H, d, J=9 Hz)

MS: 383 (M−H)⁻, 385 (M+H)⁺

EXAMPLE 9

This compound was prepared by a similar procedure to that of Example 3.

-   1-[(2S,3R)-2-benzyloxy-5-(2-fluorenyloxy)-3-pentyl]imidazole-4-carboxamide    (9).

IR (KBr, cm⁻¹): 3600–2800, 1664, 1604, 1259, 1107

NMR (CDCl₃, δ): 1.19 (3H, d, J=6 Hz), 2.05–2.70 (2H, m), 3.50–4.10 (5H,m), 4.30–4.50 (2H, m), 4.65 (1H, d, J=12 Hz), 5.36 (1H, brs), 6.82 (1H,dd, J=8.2 Hz), 6.95 (1H, brs), 6.97 (1H, d, J=2 Hz), 7.18–7.78 (12H, m)

MS: 468 (M+H)⁺

[α]_(D) ^(22.8)=+87.30° (C=0.50, EtOH)

EXAMPLE 10

This compound was prepared by a similar procedure to that of Example 2.

-   1-[(2S,3R)-5-(2-fluorenyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide    (10).

IR (KBr, cm⁻¹): 3600–2800, 1657, 1583, 1263, 1109

NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.10–2.60 (2H, m), 3.55–4.30(6H, m), 5.19 (1H, d, J=4 Hz), 6.88 (1H, dd, J=8.2 Hz), 7.02 (1H, brs),7.09 (1H, d, J=2 Hz) 7.10–7.40 (3H, m), 7.51 (1H, d, J=8 Hz), 7.60–7.80(4H, m)

MS: 378 (M+H)⁺

EXAMPLE 11

This compound was prepared by a similar procedure to that of Example 3.

-   1-[(2S,3R)-2-benzyloxy-5-(2,3-dichlorophenoxy)-3-pentyl]imidazole-4-carboxamide    (11).

IR (KBr, cm⁻¹): 3600–2800, 1672, 1265, 1090, 1057

NMR (CDCl₃, δ): 1.21 (3H, d, J=6 Hz), 2.05–2.75 (2H, m) 3.40–4.20 (3H,m), 4.40–4.60 (2H, m), 4.65 (1H, d, J=12 Hz), 5.35 (1H, brs), 6.65 (1H,dd, J=6.4 Hz), 6.91 (1H, brs), 7.00–7.40 (7H, m), 7.46 (1H, s), 7.68(1H, s)

MS: 448 (M+H)⁺ (³⁵Cl×2)

[α]D ^(22.8)=+100.90° (C=0.50, EtOH)

EXAMPLE 12

This compound was prepared by a similar procedure to that of Example 4.

-   1-[(2S,3R)-5-(2.3-dichlorophenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide    (12).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1585, 1450, 1267, 1057, 1028

NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10–2.65 (2H, m) 3.60–4.30 (4H,m), 5.20 (1H, d, J=5 Hz), 6.90–7.40 (5H, m), 7.66 (1H, s), 7.73 (1H, s)

MS: 358 (M+H)⁺ (³⁵Cl×2), 360 (M+H)⁺ (³⁵Cl−³⁷Cl)

EXAMPLE 13

This compound was prepared by a similar procedure to that of Example 3.

-   1-[(2S,3R)-2-benzyloxy-5-(7-isoquinolyloxy)-3-pentyl]imidazole-4-carboxamide    (13).

IR (KBr, cm⁻¹): 3600–2800, 1662, 1590, 1207

NMR (CDCl₃, δ): 1.20 (3H, d, J=6 Hz), 2.15–2.75 (2H, m), 3.65–4.50 (5H,m), 4.67 (1H, d, J=12 Hz), 5.37 (1H, brs), 6.92 (1H, brs), 7.06 (1H, d,J=2 Hz), 7.20–7.45 (6H, m), 7.47 (1H, s), 7.57 (1H, d, J=6 Hz), 7.60(1H, s), 7.72 (1H, d, J=9 Hz), 9.09 (1H, s)

MS: 431 (M+H)⁺

EXAMPLE 14

This compound was prepared by a similar procedure to that of Example 2.

-   1-[(2S,3R)-2-hydroxy-5-(7-isoquinolyloxy)-3-pentyl]imidazole-4-carboxamide    (14).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1593, 1267, 1207, 1142, 1092

NMR (DMSO-d₆, δ): 0.95 (3H, d, J=6 Hz), 2.20–2.65 (2H, m), 3.70–4.40(4H, m), 5.22 (1H, brs), 7.07 (1H, brs), 7.20–7.50 (3H, m), 7.70–7.85(3H, m), 7.90 (1H, d, J=9 Hz), 8.37 (1H, d, J=6 Hz), 9.18 (1H, s)

MS: 341 (M+H)⁺

Preparation 1

To a solution of ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-hydroxy-3-pentyl]imidazole-4-carboxylate(1.0 g, 2.8 mmol) in methanol (15 ml) was added aqueous 28% NH₃ solution(15 ml). And the mixture was heated at 100° C. in a sealed steel tubefor 15 h. After cooling, the reaction mixture was concentrated in vacuo.The residue was purified by silica gel (35 g) chromatography elutingwith chloroform/methanol (25:1 to 15:1) to give1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-hydroxy-3-pentyl]imidazole-4-carboxamide(769.5 mg, 83.8%) as a white amorphous solid.

IR (KBr, cm⁻¹): 3600–2800, 1664, 1604, 1417, 1261, 1143, 1092, 1058

NMR (DMSO-d₆, δ) 0.00 (3H, s), 0.03 (3H, s), 0.86 (9H, s), 0.93 (3H, d,J=6 Hz), 1.80–2.15 (2H, m), 2.95–3.45 (2H, m), 3.90–4.25 (2H, m), 4.55(1H, t, J=5 Hz), 7.02 (1H, brs), 7.25 (1H, brs), 7.64 (1H, s), 7.67 (1H,s)

MS: 327 (M−H)⁻

EXAMPLE 15

This compound was prepared by a similar procedure to that of Example 3.

-   1-[(2S,3R)-5-(6-bromo-2-naphthyloxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide    (15).

NMR (CDCl₃, δ): 0.05 (3H, s), 0.08 (3H, s), 0.93 (9H, s), 1.11 (3H, d,J=6 Hz), 2.10–2.70 (2H, m), 3.65–4.35 (4H, m), 5.35 (1H, brs), 6.90 (1H,brs), 6.95 (1H, d, J=2 Hz), 7.09 (1H, dd, J=9.2 Hz), 7.35–7.80 (5H, m),7.90 (1H, s)

MS: 532 (M+H)⁺ (⁷⁹Br), 534 (M+H)⁺ (⁸¹Br)

EXAMPLE 16

To an ice cooled solution of1-[(2S,3R)-5-(6-bromo-2-naphthyloxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide(120 mg, 0.225 mmol) in THF (5 ml) was added dropwise 1.0 Mtetra-n-butylammonium fluoride in THF (338 μl). After the addition wascompleted, the reaction mixture was stirred at ice-bath temperature for2 hours. The reaction was quenched by addition of 25% aqueous AcONH₄ (5ml) and H₂O (10 ml) The resulting mixture was stirred for severalminutes and then extracted with ethyl acetate (30 ml). The organic layerwas washed with brine, dried (sodium sulfate) and concentrated underreduced pressure. The residue was purified by silica gel (4 g) columnchromatography eluting with chloroform/methanol (100:1 to 20:1) to give1-[(2S,3R)-5-(6-bromo-2-naphthyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide(16) (58.6 mg, 62.2%) as a white solid.

IR (KBr, cm⁻¹): 3600–2800, 1655, 1593, 1498, 1261, 1207, 1126, 1086

NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.10–2.65 (2H, m), 3.60–4.35(4H, m), 5.20 (1H, d, J=5 Hz), 7.02 (1H, brs), 7.10–7.35 (3H, m), 7.54(1H, dd, J=9.2 Hz), 7.60–7.90 (4H, m), 8.09 (1H, d, J=2 Hz)

MS: 418 (M+H)⁺ (⁷⁹Br), 420 (M+H)⁺ (⁸¹Br)

EXAMPLE 17

This compound was prepared by a similar procedure to that of Example 15.

-   1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(3,4-dimethylphenoxy)-3-pentyl]imidazole-4-carboxamide    (17).

NMR (CDCl₃, δ): 0.02 (3H, s), 0.06 (3H, s), 0.90 (9H, s), 1.09 (3H, d,J=6 Hz), 2.00–2.60 (8H, m), 3.40–4.30 (4H, m), 5.32 (1H, brs), 6.53 (1H,dd, J=8.3 Hz), 6.60 (1H, d, J=3 Hz), 6.93 (1H, brs), 6.98 (1H, d, J=8Hz), 7.41 (1H, s), 7.62 (1H, s)

MS: 432 (M+H)⁺

EXAMPLE 18

This compound was prepared by a similar procedure to that of Example 16.

-   1-[(2S,3R)-5-(3,4-dimethylphenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide    (18).

IR (KBr, cm⁻¹): 3600–2800, 1660, 1599, 1500, 1412, 1248, 1119, 1090,1053

NMR (DMSO-d₆, δ): 0.92 (3H, d, J=6 Hz), 2.00–2.55 (8H, m), 3.40–4.30(4H, m), 5.16 (1H, d, J=5 Hz), 6.55 (1H, dd, J=8, 2.5 Hz), 6.64 (1H, d,J=2.5 Hz), 6.97 (1H, d, J=8 Hz), 7.02 (1H, brs), 7.24 (1H, brs), 7.67(1H, s) 7.71 (1H, s)

MS: 318 (M+H)⁺

EXAMPLE 19

This compound was prepared by a similar procedure to that of Example 15.

-   1-[(2S,3R)-5-(1,1′-biphenyl-3-yloxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide    (19).

NMR (CDCl₃, δ): 0.03 (3H, s), 0.06 (3H, s), 0.91 (9H, s), 1.11 (3H, d,J=6 Hz), 2.00–2.65 (2H, m), 3.55–4.35 (4H, m), 5.36 (1H, brs), 6.70–7.05(3H, m), 7.10–7.75 (9H, m)

MS: 480 (M+H)⁺

EXAMPLE 20

This compound was prepared by a similar procedure to that of Example 16.

-   1-[(2S,3R)-5-(1,1′-biphenyl-3-yloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide    (20).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1595, 1473, 1415, 1238 1088

NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10–2.60 (2H, m), 3.60–4.35(4H, m), 5.18 (1H, d, J=5 Hz), 6.75–750 (9H, m), 7.55–7.85 (4H, m)

MS: 366 (M+H)⁺

EXAMPLE 21

This compound was prepared by a similar procedure to that of Example 15.

-   1-[(2S,3R)-5-(1,1′-biphenyl-2-yloxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide    (21).

NMR (CDCl₃, δ): −0.06 (3H, s), 0.00 (3H, s), 0.87 (9H, s) 0.93 (3H, d,J=6 Hz), 1.85–2.55 (2H, m), 3.30–4.20 (4H, m), 5.30 (1H, brs), 6.80–7.10(3H, m), 7.15–7.75 (9H, m)

MS: 480 (M+H)⁺

EXAMPLE 22

This compound was prepared by a similar procedure to that of Example 16.

-   1-[(2S,3R)-5-(1,1′-biphenyl-2-yloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide    (22).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1593, 1479, 1427, 1261, 1234, 1122,1088, 1059

NMR (DMSO-d₆, δ): 0.86 (3H, d, J=6 Hz), 1.95–2.50 (2H, m), 3.40–4.10(4H, m), 5.13 (1H, d, J=5 Hz), 6.85–7.10 (3H, m), 7.15–7.70 (10H, m)

MS: 366 (M+H)⁺

EXAMPLE 23

This compound was prepared by a similar procedure to that of Example 15.

-   1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(3-isoquinolyloxy)-3-pentyl]imidazole-4-carboxamide    (23).

IR (KBr, cm⁻¹): 3600–2800, 1666, 1591, 1261, 1099

NMR (CDCl₃, δ): 0.01 (3H, s), 0.06 (3H, s), 0.89 (9H, s), 1.09 (3H, d,J=6 Hz), 2.10–2.70 (2H, m), 3.90–4.50 (4H, m), 5.34 (1H, brs), 6.90 (1H,brs), 6.92 (1H, s), 7.30–7.75 (5H, m), 7.87 (1H, d, J=8 Hz), 8.90 (1H,s)

MS: 455 (M+H)⁺

EXAMPLE 24

This compound was prepared by a similar procedure to that of Example 16.

-   1-[(2S,3R)-2-hydroxy-5-(3-isoquinolyloxy)-3-pentyl]imidazole-4-carboxamide    (24).

IR (KBr, cm⁻¹): 3600–2800, 1660, 1591, 1450, 1267, 1234, 1130, 1090,1051

NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.15–2.60 (2H, m) 3.65–4.35 (4H,m), 5.18 (1H, d, J=5 Hz), 7.03 (1H, brs), 7.11 (1H, s), 7.25 (1H, brs),7.35–7.85 (5H, m), 8.00 (1H, d, J=8 Hz), 9.00 (1H, s)

MS: 341 (M+H)⁺

Preparation 2

Under N₂, to a suspension of benzyltriphenylphosphonium bromide (980 mg,2.26 mmol) in acetonitrile (10 ml) was added DBU at room temperature.After stirring for 10 min.,5-(benzyloxy)-1-methyl-1H-indole-2-carbaldehyde (500 mg, 1.88 mmol) wasadded and the mixture was stirred overnight at room temperature. Theresulting mixture was filtered and washed with acetonitrile. Thefiltrate was concentrated in vacuo and then the residue was purified bysilica gel (70 g) chromatography eluted with chloroform to give5-(benzyloxy)-1-methyl-2-(2-phenylethenyl)-1H-indole (221 mg, 34.5%).

IR (KBr, cm⁻¹): 3050, 2860, 1612, 1456, 1238, 1029

NMR (CDCl₃, δ): 3.79 (3H, s), 5.11 (2H, s), 6.85–7.60 (16H, m)

MS: 340 (M+H)⁺

Preparation 3

To a solution of 5-(benzyloxy)-1-methyl-2-(2-phenylethenyl)-1H-indole(204 mg, 0.601 mmol) in EtOH (5 ml) and THF (5 ml) was added 10%palladium on carbon (50 mg). The resulting mixture was stirred underhydrogen (2 atm) for 15 h at room temperature. The mixture was filteredthrough Celite and washed with EtOH. The filtrate was concentrated invacuo and then the residue was purified by silica gel (4.5 g)chromatography eluted with chloroform to give1-methyl-2-(2-phenylethyl)-1H-indol-5-ol (110 mg, 72.8%).

NMR (CDCl₃, δ): 3.02 (4H, s), 3.57 (3H, s), 4.42 (1H, s) 6.19 (1H, s),6.73 (1H, dd, J=9.2 Hz), 6.96 (1H, d, J=2 Hz), 7.11 (1H, d, J=9 Hz),7.15–7.40 (5H, m)

MS: 252 (M+H)⁺

EXAMPLE 25

This compound was prepared by a similar procedure to that of Example 15.

-   1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[1-methyl-2-(2-phenylethyl)-1H-indol-5-yloxy]-3-pentyl}imidazole-4-carboxamide    (25).

NMR (CDCl₃, δ): 0.02 (3H, s), 0.06 (3H, s), 0.91 (9H, s) 1.10 (3H, d,J=6 Hz), 2.00–2.65 (2H, m), 3.02 (4H, s), 3.56 (3H, s), 3.57–4.40 (4H,m), 5.33 (1H, brs), 6.20 (1H, s), 6.73 (1H, dd, J=9.2 Hz), 6.91 (1H, d,J=2 Hz), 6.94 (1H, brs), 7.11 (1H, d, J=9 Hz), 7.15–7.35 (5H, m), 7.44(1H, s), 7.64 (1H, s)

MS: 561 (M+H)⁺

EXAMPLE 26

This compound was prepared by a similar procedure to that of Example 16.

-   1-{(2S,3R)-2-hydroxy-5-[1-methyl-2-(2-phenylethyl)-1H-indol-5-yloxy]-3-pentyl}imidazole-4-carboxamide    (26).

NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.05–2.65 (2H, m), 2.98 (4H, s),3.45–4.35 (7H, m), 5.17 (1H, d, J=5 Hz), 6.12 (1H, s), 6.65 (1H, dd,J=9.2 Hz), 6.86 (1H, d, J=2 Hz), 7.03 (1H, brs), 7.10–7.35 (7H, m), 7.69(1H, s), 7.74 (1H, s)

MS: 447 (M+H)⁺

EXAMPLE 27

This compound was prepared by a similar procedure to that of Example 15.

-   1-[(2S,3R)-5-(1,1′-biphenyl-4-yloxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide    (27).

NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.90 (9H, s) 1.11 (3H, d,J=6 Hz), 2.00–2.65 (2H, m), 3.55–4.35 (4H, m), 5.35 (1H, brs), 6.87 (2H,d, J=7 Hz), 6.90 (1H, brs), 7.25–7.60 (8H, m), 7.64 (1H, s)

MS: 480 (M+H)⁺

EXAMPLE 28

This compound was prepared by a similar procedure to that of Example 16.

-   1-[(2S,3R)-5-(1,1′-biphenyl-4-yloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide    (28).

mp. 191–193° C.

IR (KBr, cm⁻¹): 3600–2800, 1655, 1602, 1485, 1243, 1124, 1084, 1038

NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10–2.60 (2H, m), 3.50–4.30(4H, m), 5.19 (1H, d, J=5 Hz), 6.85–7.10 (3H, m), 7.15–7.65 (8H, m),7.70 (1H, s), 7.75 (1H, s)

MS: 366 (M+H)⁺

EXAMPLE 29

This compound was prepared by a similar procedure to that of Example 15.

-   1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(3-tert-butylphenoxy)-3-pentyl]imidazole-4-carboxamide.

NMR (CDCl₃, δ): 0.02 (3H, s), 0.06 (3H, s), 0.91 (9H, s) 1.10 (3H, d,J=6 Hz), 1.28 (9H, s), 2.00–2.60 (2H, m), 3.55–4.35 (4H, m), 5.36 (1H,brs), 6.50–7.25 (5H, m), 7.43 (1H, s), 7.63 (1H, s)

MS: 460 (M+H)⁺

EXAMPLE 30

This compound was prepared by a similar procedure to that of Example 16.

-   1-[(2S,3R)-5-(3-tert-butylphenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide    (30).

IR (KBr, cm⁻¹): 3600–2800, 1662, 1608, 1572, 1485, 1427, 1271, 1238,1128, 1093

NMR (DMSO-d₆, δ): 0.92 (3H, d, J=6 Hz), 2.05–2.60 (2H, m), 3.50–4.30(4H, m), 5.17 (1H, d, J=5 Hz), 6.55–7.35 (6H, m), 7.69 (1H, s), 7.74(1H, s)

MS: 346 (M+H)⁺

EXAMPLE 31

This compound was prepared by a similar procedure to that of Example 15.

-   1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide    (31).

NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.11 (3H, d,J=6 Hz), 2.00–2.65 (2H, m), 3.55–4.35 (4H, m), 5.36 (1H, brs), 6.65–7.35(8H, m), 7.43 (1H, s), 7.64 (1H, s)

MS: 486 (M+H)⁺

EXAMPLE 32

This compound was prepared by a similar procedure to that of Example 16.

-   1-{(2S,3R)-2-hydroxy-5-[3-(2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide    (32).

IR (KBr, cm⁻¹): 3600–2800, 1657, 1595, 1483, 1419, 1265, 1232, 1090,1057

NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10–2.60 (2H, m) 3.55–4.35 (4H,m), 5.18 (1H, d, J=5. Hz), 6.70–7.60 (9H, m), 7.71 (1H, s), 7.76 (1H, s)

MS: 372 (M+H)⁺

EXAMPLE 33

This compound was prepared by a similar procedure to that of Example 15.

-   1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[2-(2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide    (33).

NMR (CDCl₃, δ): 0.00 (3H, s), 0.05 (3H, s), 0.91 (9H, s), 1.08 (3H, d,J=6 Hz), 2.00–2.75 (2H, m), 3.55–4.45 (4H, m), 5.31 (1H, brs), 6.75–7.45(8H, m), 7.55–7.70 (2H, m)

MS: 486 (M+H)⁺

EXAMPLE 34

This compound was prepared by a similar procedure to that of Example 16.

-   1-{(2S,3R)-2-hydroxy-5-[2-(2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide    (34).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1592, 1483, 1446, 1415, 1238, 1119,1090, 1057

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6 Hz), 2.10–2.70 (2H, m), 3.60–4.40(4H, m), 5.21 (1H, d, J=5 Hz), 6.90–7.35 (6H, m), 7.50–7.80 (5H, m)

MS: 372 (M+H)⁺

Preparation 4

To a stirred solution of 2-benzyl-4-(3-methoxyphenyl)thiazole (1.0 g,3.55 mmol) in CH₂Cl₂ (20 ml) was added a solution of 1.0 M BBr₃ inCH₂Cl₂ (4.26 ml) at −78° C. The resulting mixture was stirred at −78° C.for 30 min and then allowed to warm up to room temperature. The mixturewas quenched with water and extracted with ether. The organic layer waswashed with brine, dried (magnesium sulfate) and evaporated in vacuo.The residue was triturated with chloroform and dried under reducedpressure to give 3-(2-benzylthiazol-4-yl)phenol (760 mg, 80%).

IR (KBr, cm⁻¹): 3600–2600, 1599, 1498, 1440, 1246, 1176, 1144, 1070

NMR (DMSO-d₆, δ): 4.38 (2H, s), 6.65–6.80 (1H, m), 7.10–7.45 (8H, m),7.86 (1H, s), 9.47 (1H, brs)

MS: 268 (M+H)⁺

EXAMPLE 35

This compound was prepared by a similar procedure to that of Example 15.

-   1-{(2S,3R)-5-[3-(2-benzylthiazol-4-yl)phenoxy]-2-(tert-butyldimethylsilyloxy)-3-pentyl}imidazole-4-carboxamide    (35).

NMR (CDCl₃, δ): 0.03 (3H, s), 0.06 (3H, s), 0.91 (9H, s), 1.11 (3H, d,J=6 Hz), 2.05–2.65 (2H, m), 3.60–4.45 (6H, m), 5.32 (1H, brs), 6.70–7.80(1H, m), 6.92 (1H, brs), 7.20–7.50 (10H, m), 7.65 (1H, s)

MS: 577 (M+H)⁺

EXAMPLE 36

This compound was prepared by a similar procedure to that of Example 16.

-   1-{(2S,3R)-5-[3-(2-benzylthiazol-4-yl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide    (36).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1592, 1495, 1460, 1415, 1240, 1119,1090, 1059

NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.10–2.60 (2H, m), 3.50–4.30(4H, m), 4.38 (2H, s), 5.18 (1H, d, J=5 Hz), 6.70–7.55 (11H, m), 7.71(1H, s), 7.76 (1H, s), 7.96 (1H, s)

MS: 463 (M+H)⁺

EXAMPLE 37

This compound was prepared by a similar procedure to that of Example 15.

-   1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(2-phenylthiazol-4-yl)phenoxy]-3-pentyl}imidazole-4-carboxamide    (37).

NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.92 (9H, s), 1.12 (3H, d,J=6 Hz), 2.00–2.65 (2H, m), 3.60–4.40 (4H, m), 5.34 (1H, brs), 6.70–7.00(2H, m), 7.20–7.75 (9H, m), 7.95–8.10 (2H, m)

MS: 563 (M+H)⁺

EXAMPLE 38

This compound was prepared by a similar procedure to that of Example 16.

-   1-{(2S,3R)-2-hydroxy-5-[3-(2-phenylthiazol-4-yl)phenoxy]-3-pentyl}imidazole-4-carboxamide    (38).

IR (KBr, cm¹⁻): 3600–2800, 1658, 1593, 1479, 1240, 1169, 1090, 1059

NMR (DMSO-d₆, δ): 0.95 (3H, d, J=6 Hz), 2.10–2.65 (2H, m), 3.55–4.35(4H, m), 5.20 (1H, d, J=5 Hz), 6.75–6.95 (1H, m), 7.03 (1H, brs), 7.25(1H, brs), 7.35 (1H, t, J=8 Hz), 7.40–7.69 (5H, m), 7.72 (1H, s), 7.77(1H, s), 7.95–8.10 (2H, m), 8.19 (1H, s)

MS: 449 (M+H)⁺

EXAMPLE 39

This compound was prepared by a similar procedure to that of Example 15.

-   1-[(2S,3R)-5-(3-bromophenoxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide    (39).

NMR (CDCl₃, δ): 0.02 (3H, s), 0.06 (3H, s), 0.91 (9H, s), 1.09 (3H, d,J=6 Hz), 2.00–2.65 (2H, m), 3.50–4.30 (4H, m), 5.36 (1H, brs), 6.60–7.15(5H, m), 7.41 (1H, s), 7.62 (1H, s)

MS: 482 (M+H)⁺ (⁷⁹Br), 484 (M+H)⁺ (⁸¹Br)

EXAMPLE 40

This compound was prepared by a similar procedure to that of Example 16.

-   1-[(2S,3R)-5-(3-bromophenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide    (40).

IR (KBr, cm⁻¹): 3600–2800, 1664, 1593, 1236, 1092

NMR (DMSO-d₆, δ): 0.92 (3H, d, J=6 Hz), 2.05–2.60 (2H, m), 3.50–4.30(4H, m), 5.18 (1H, d, J=5 Hz), 6.80–7.35 (6H, m), 7.69 (1H, s), 7.74(1H, s)

MS: 368 (M+H)⁺ (⁷⁹Br), 370 (M+H)⁺ (⁸¹Br)

EXAMPLE 41

To a solution of1-[(2S,3R)-5-(3-bromophenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamidein DME (5 ml) was added Pd(PPh₃)₄ (29.3 mg, 0.025 mmol)at ambienttemperature under N₂. After stirring for 20 min.,benzothiophene-2-boronic acid (54.2 mg, 0.304 mmol) and a solution ofNa₂CO₃ (40.3 mg, 0.38 mmol) in H₂O (1 ml) were added and the mixture wasrefluxed for 3 h. The mixture was cooled to room temperature andpartitioned between ethyl acetate (20 ml) and H₂O. The organic layer waswashed successively with saturated NaHCO₃ aqueous solution, H₂O and thenbrine, dried (sodium sulfate) and evaporated in vacuo. The residue waspurified by silica gel chromatography eluting with chloroform/methanol(100:1 to 20:1) to give1-{(2S,3R)-5-[3-(2-benzo[b]thiophenyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide(41) (66.9 mg, 62.6%).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1594, 1432, 1261, 1171, 1092

NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.10–2.60 (2H, m), 3.50–4.35(4H, m), 5.20 (1H, d, J=5 Hz), 6.80–7.50 (8H, m), 7.65–8.05 (5H, m)

MS: 422 (M+H)⁺

EXAMPLE 42

This compound was prepared by a similar procedure to that of Example 15.

-   1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(4-morpholinyl)phenoxy]-3-pentyl}imidazole-4-carboxamide    (42).

IR (KBr, cm⁻¹): 3600–2800, 1666, 1600, 1259, 1191, 1118

NMR (CDCl₃, δ): 0.02 (3H, s), 0.06 (3H, s), 0.91 (9H, s), 1.09 (3H, d,J=6 Hz), 2.00–2.60 (2H, m), 3.13 (4H, t, J=5 Hz), 3.50–4.30 (8H, m),5.34 (1H, brs), 6.20–6.65 (3H, m), 6.92 (1H, brs), 7.13 (1H, t, J=8 Hz),7.41 (1H, s), 7.62 (1H, s)

MS: 489 (M+H)⁺

EXAMPLE 43

This compound was prepared by a similar procedure to that of Example 16.

-   1-{(2S,3R)-2-hydroxy-5-[3-(4-morpholinyl)phenoxy]-3-pentyl}imidazole-4-carboxamide    (43).

IR (KBr, cm⁻¹): 3600–2800, 1660, 1600, 1493, 1450, 1261, 1190, 1117

NMR (DMSO-d₆, δ): 0.92 (3H, d, J=6 Hz), 2.05–2.55 (2H, m), 3.04 (4H, t,J=5 Hz), 3.55–4.30 (8H, m), 5.16 (1H, brs), 6.20–6.65 (3H, m), 6.90–7.15(2H, m), 7.24 (1H, brs), 7.68 (1H, s), 7.72 (1H, s)

MS: 375 (M+H)⁺

Preparation 5

To a solution of 3-iodophenol (1.0 g, 4.55 mmol) in DME (10 ml) wasadded Pd(PPh₃)₄ (263 mg, 0.227 mmol) at ambient temperature under N₂.After stirring for 20 min., 5-chlorothiophene-2-boronic acid (886 mg,5.45 mmol) and a solution of Na₂CO₃ (723 mg, 6.82 mmol) in H₂O (3 ml)were added and the mixture was refluxed for 2 h. The mixture was cooledto room temperature and partitioned between ethyl acetate (30 ml) andH₂O. The organic layer was washed with saturated NaHCO₃ aqueoussolution, H₂O and then brine, dried (sodium sulfate) and evaporated invacuo. The residue was purified by silica gel (15 g) chromatographyeluting with hexane/ethyl acetate (10:1) to give3-(5-chloro-2-thienyl)phenol (0.88 g, 91.9%).

IR (KBr, cm⁻¹): 3600–2800, 1599, 1454, 1250, 1217, 1088, 787

NMR (CDCl₃, δ): 4.87 (1H, s), 6.70–6.80 (1H, m), 6.88 (1H, d, J=4 Hz),6.98 (1H, t, J=2 Hz), 7.00–7.32 (3H, m)

MS: 209 (M−H)⁻ (³⁵Cl), 211 (M−H)⁻ (³⁷Cl)

EXAMPLE 44

This compound was prepared by a similar procedure to that of Example 15.

-   1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(5-chloro-2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide    (44).

NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.11 (3H, d,J=6 Hz), 2.05–2.65 (2H, m), 3.55–4.33 (4H, m), 5.32 (1H, brs), 6.65–7.35(7H, m), 7.43 (1H, s), 7.64 (1H, s)

MS: 520 (M+H)⁺ (³⁵Cl), 522 (M+H)⁺ (³⁷Cl)

EXAMPLE 45

This compound was prepared by a similar procedure to that of Example 16.

-   1-{(2S,3R)-5-[3-(5-chloro-2-thienyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide    (45).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1593, 1485, 1425, 1265, 1088

NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10–2.65 (2H, m), 3.50–4.30(4H, m), 5.18 (1H, d, J=5 Hz), 6.70–7.45 (8H, m), 7.70 (1H, s), 7.75(1H, s)

MS: 406 (M+H)⁺ (³⁵Cl), 408 (M+H)⁺ (³⁷Cl)

Preparation 6

This compound was prepared by a similar procedure to that of Preparation5.

-   3-(5-Methyl-2-thienyl)phenol.

IR (KBr, cm⁻¹): 3600–2800, 1585, 1444, 1223, 1186, 847, 779

NMR (CDCl₃, δ): 2.50 (3H, s), 4.81 (1H, s), 6.60–6.80 (2H, m), 6.95–7.30(4H, m)

MS: 189 (M−H)⁻

EXAMPLE 46

This compound was prepared by a similar procedure to that of Example 15.

-   1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(5-methyl-2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide    (46).

NMR (CDCl₃, δ): 0.03 (3H, s), 0.06 (3H, s), 0.91 (9H, s), 1.10 (3H, d,J=6 Hz), 2.00–2.65 (5H, m), 3.55–4.35 (4H, m), 5.34 (1H, brs), 6.60–7.30(7H, m), 7.43 (1H, s), 7.64 (1H, s)

MS: 500 (M+H)⁺

EXAMPLE 47

This compound was prepared by a similar procedure to that of Example 16.

-   1-{(2S,3R)-2-hydroxy-5-[3-(5-methyl-2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide    (47).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1599, 1495, 1427, 1267, 1228, 1090,1053

NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10–2.60 (5H, m), 3.50–4.30(4H, m), 5.18 (1H, d, J=5 Hz), 6.65–7.35 (8H, m), 7.70 (1H, s), 7.75(1H, s)

MS: 386 (M+H)⁺

EXAMPLE 48

This compound was prepared by a similar procedure to that of Example 15.

-   1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(2-quinolyloxy)-3-pentyl]imidazole-4-carboxamide    (48).

NMR (CDCl₃, δ): 0.01 (3H, s), 0.06 (3H, s), 0.88 (9H, s), 1.07 (3H, d,J=6 Hz), 2.10–2.70 (2H, m), 3.90–4.65 (4H, m), 5.46 (1H, brs), 6.83 (1H,d, J=9 Hz), 6.95 (1H, brs), 7.10–7.85 (6H, m), 7.98 (1H, d, J=9 Hz)

MS: 455 (M+H)⁺

EXAMPLE 49

This compound was prepared by a similar procedure to that of Example 16.

-   1-[(2S,3R)-2-hydroxy-5-(2-quinolyloxy)-3-pentyl]imidazole-4-carboxamide    (49).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1608, 1425, 1267, 1238, 1111, 1088

NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.20–2.45 (2H, m), 3.75–4.45(4H, m), 5.17 (1H, d, J=5 Hz), 6.95 (1H, d, J=9 Hz), 7.05 (1H, brs),7.25 (1H, brs), 7.35–7.95 (6H, m), 8.21 (1H, d, J=9 Hz)

MS: 341 (M+H)⁺

EXAMPLE 50

This compound was prepared by a similar procedure to that of Example 15.

-   1-{(2S,3R)-5-[3-(2-benzoxazolyl)phenoxy]-2-(tert-butyldimethylsilyloxy)-3-pentyl}imidazole-4-carboxamide    (50).

IR (KBr, cm⁻¹): 3600–2800, 1666, 1558, 1454, 1242, 1103, 1038

NMR (CDCl₃, δ): 0.04 (3H, s), 0.07 (3H, s), 0.92 (9H, s), 1.12 (3H, d,J=6 Hz), 2.05–2.70 (2H, m), 3.65–4.35 (4H, m), 5.33 (1H, brs), 6.80–7.05(2H, m), 7.30–7.70 (4H, m), 7.52–7.90 (5H, m)

MS: 521 (M+H)⁺

EXAMPLE 51

This compound was prepared by a similar procedure to that of Example 16.

-   1-{(2S,3R)-5-[3-(2-benzoxazolyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide    (51).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1592, 1554, 1450, 1236, 1088

NMR (DMSO-d₆, δ): 0.95 (3H, d, J=6 Hz), 2.10–2.60 (2H, m) 3.55–4.35 (4H,m), 5.20 (1H, d, J=5 Hz), 7.02 (1H, brs), 7.09–7.19 (1H, m), 7.24 (1H,brs), 7.33–7.90 (9H, m)

MS: 407 (M+H)⁺

EXAMPLE 52

This compound was prepared by a similar procedure to that of Example 15.

-   1-{(2S,3R)-5-[3-(2-benzofuranyl)phenoxy]-2-(tert-butyldimethylsilyloxy)-3-pentyl}imidazole-4-carboxamide    (52).

NMR (CDCl₃, δ): 0.04 (3H, s), 0.07 (3H, s), 0.92 (9H, s), 1.12 (3H, d,J=6 Hz), 2.05–2.70 (2H, m), 3.60–4.35 (4H, m), 5.36 (1H, brs), 6.70–6.85(1H, m), 6.92 (1H, brs), 7.01 (1H, s), 7.15–7.70 (10H, m)

MS: 520 (M+H)⁺

EXAMPLE 53

This compound was prepared by a similar procedure to that of Example 16.

-   1-{(2S,3R)-5-[3-(2-benzofuranyl)phenoxy]-2-hydroxy-3-pentyl)imidazole-4-carboxamide    (53).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1599, 1568, 1450, 1261, 1234, 1090,1055

NMR (DMSO-d₆, δ): 0.95 (3H, d, J=6 Hz), 2.10–2.60 (2H, m) 3.60–4.35 (4H,m), 5.19 (1H, d, J=5 Hz), 6.80–6.95 (1H, m), 7.02 (1H, brs), 7.15–7.53(7H, m), 7.56–7.85 (4H, m)

MS: 406 (M+H)⁺

EXAMPLE 54

This compound was prepared by a similar procedure to that of Example 15.

1-{2S,3R}-5-[3-(1H-benzimidazol-2-yl)phenoxy]-2-(tert-butyldimethylsilyloxy)-3-pentyl}imidazole-4-carboxamide(54).

MS: 520 (M+H)⁺

EXAMPLE 55

This compound was prepared by a similar procedure to that of Example 16.

-   1-{(2S,3R)-5-[3-(1H-benzimidazol-2-yl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide    (55).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1599, 1460, 1267, 1236, 1095

NMR (DMSO-d₆, δ): 0.95 (3H, d, J=6 Hz), 2.10–2.60 (2H, m), 3.60–4.35(4H, m), 5.21 (1H, d, J=5 Hz), 6.90–7.30 (5H, m), 7.42 (1H, t, J=8 Hz),7.50–7.85 (6H, m)

MS: 406 (M+H)⁺

Preparation 7

This compound was prepared by a similar procedure to that of Preparation5.

-   4′-Chloro-1,1′-biphenyl-3-ol.

IR (KBr, cm⁻¹): 3600–2800, 1593, 1475, 1292, 1201, 1083, 825, 777

NMR (CDCl₃, δ): 4.93 (1H, s), 6.75–6.90 (1H, m), 7.02 (1H, t, J=2 Hz),7.05–7.60 (6H, m)

MS: 203 (M−H)³¹ (³⁵Cl), 205 (M−H)⁻ (³⁷Cl)

EXAMPLE 56

This compound was prepared by a similar procedure to that of Example 15.

-   1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(4′-chloro-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide    (56).

NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.11 (3H, d,J=6 Hz), 2.00–2.65 (2H, m), 3.55–4.35 (4H, m), 5.34 (1H, brs), 6.65–7.18(4H, m), 7.20–7.55 (6H, m), 7.64 (1H, s)

MS: 514 (M+H)⁺ (³⁵Cl), 516 (M+H)⁺ (³⁷Cl)

EXAMPLE 57

This compound was prepared by a similar procedure to that of Example 16.

-   1-{(2S,3R)-5-[(4′-chloro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide    (57).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1593, 1473, 1263, 1238, 1091, 1060

NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10–2.60 (2H, m), 3.55–4.30(4H, m), 5.17 (1H, d, J=5 Hz), 6.75–7.55 (8H, m), 7.60–7.85 (4H, m)

MS: 400 (M+H)⁺ (³⁵Cl), 402 (M+H)⁺ (³⁷Cl)

Preparation 8

This compound was prepared by a similar procedure to that of Preparation5.

-   3′-Chloro-1,1′-biphenyl-3-ol.

IR (KBr, cm⁻¹): 3600–2800, 1595, 1466, 1238, 1199, 1092, 1045, 773

NMR (CDCl₃, δ): 4.91 (1H, s), 6.75–6.90 (1H, m), 7.03 (1H, t, J=2 Hz),7.08–7.60 (6H, m)

MS: 203 (M−H)⁻ (³⁵Cl), 205 (M−H)⁻ (³⁷Cl)

EXAMPLE 58

This compound was prepared by a similar procedure to that of Example 15.

-   1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(3′-chloro-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide    (58).

NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.91 (9H, s) 1.11 (3H, d,J=6 Hz), 2.00–2.65 (2H, m), 3.55–4.35 (4H, m), 5.33 (1H, brs), 6.70–7.18(4H, m), 7.20–7.45 (5H, m), 7.53 (1H, s), 7.64 (1H, s)

MS: 514 (M+H)⁺ (³⁵Cl), 516 (M+H)⁺ (³⁷Cl)

EXAMPLE 59

This compound was prepared by a similar procedure to that of Example 16.

-   1-{(2S,3R)-5-[(3′-chloro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide    (59).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1593, 1465, 1263, 1205, 1090, 1085,1045

NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10–2.60 (2H, m), 3.55–4.30(4H, m), 5.18 (1H, d, J=5 Hz), 6.80–7.80 (12H, m)

MS: 400 (M+H)⁺ (³⁵Cl), 402 (M+H)⁺ (³⁷Cl)

Preparation 9

This compound was prepared by a similar procedure to that of Preparation5.

-   2′-Chloro-1,1′-biphenyl-3-ol.

IR (KBr, cm⁻¹) 3600–2800, 1589, 1462, 1240, 1190, 1078, 1039

NMR (CDCl₃, δ): 4.90 (1H, s), 6.75–7.05 (3H, m), 7.15–7.52 (5H, m)

MS: 203 (M−H)⁻ (³⁵Cl), 205 (M−H)⁻ (³⁷Cl)

EXAMPLE 60

This compound was prepared by a similar procedure to that of Example 15.

-   1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(2′-chloro-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide    (60).

NMR (CDCl₃, δ): 0.02 (3H, s), 0.06 (3H, s), 0.91 (9H, s), 1.10 (3H, d,J=6 Hz), 2.00–2.65 (2H, m), 3.55–4.35 (4H, m), 5.33 (1H, brs), 6.75–7.05(4H, m), 7.20–7.50 (6H, m), 7.63 (1H, s)

MS: 514 (M+H)⁺ (³⁵Cl), 516 (M+H)⁺ (³⁷Cl)

EXAMPLE 61

This compound was prepared by a similar procedure to that of Example 16.

-   1-{(2S,3R)-5-[(2′-chloro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide    (61).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1589, 1464, 1259, 1203, 1124, 1085,1045

NMR (DMSO-d₆, δ): 0.92 (3H, d, J=6 Hz), 2.10–2.60 (2H, m) 3.55–4.30 (4H,m), 5.1.6 (1H, d, J=5 Hz), 6.80–7.05 (4H, m), 7.23 (1H, brs), 7.28–7.60(5H, m), 7.69 (1H, s), 7.74 (1H, s)

MS: 400 (M+H)⁺ (³⁵Cl), 402 (M+H) ⁺ (³⁷Cl)

EXAMPLE 62

This compound was prepared by a similar procedure to that of Example 15.

-   1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(4′-methoxy-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide    (62).

IR (KBr, cm⁻¹): 3600–2800, 1666, 1602, 1251, 1103, 1034

NMR (CDCl₃, δ): 0.02 (3H, s), 0.06 (3H, s), 0.91 (9H, s) 1.10 (3H, d,J=6 Hz), 2.00–2.65 (2H, m), 3.55–4.35 (7H, m), 5.32 (1H, brs), 6.65–7.55(10H, m), 7.64 (1H, s)

MS: 510 (M+H)⁺

EXAMPLE 63

This compound was prepared by a similar procedure to that of Example 16.

-   1-{(2S,3R)-2-hydroxy-5-[(4′-methoxy-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide    (63).

IR (KBr, cm⁻): 3600–2800, 1660, 1601, 1479, 1410, 1248, 1205, 1184, 1024

NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10–2.60 (2H, m), 3.55–4.30(7H, m), 5.17 (1H, d, J=5 Hz), 6.70–7.35 (8H, m), 7.57 (2H, d, J=9 Hz),7.70 (1H, s), 7.75 (1H, s)

MS: 396 (M+H)⁺

Preparation 10

This compound was prepared by a similar procedure to that of Preparation5.

-   3′-Methoxy-1,1′-biphenyl-3-ol.

IR (KBr, cm⁻¹: 3600–2800, 1599, 1238, 1161, 1088, 802

NMR (CDCl₃, δ): 3.86 (3H, s), 4.88 (1H, s), 6.75–6.95 (2H, m), 7.00–7.40(6H, m)

MS: 199 (M−H)⁻

EXAMPLE 64

This compound was prepared by a similar procedure to that of Example 15.

-   1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(3′-methoxy-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide    (64).

NMR (CDCl₃, δ): 0.02 (3H, s), 0.06 (3H, s), 0.91 (9H, s), 1.10 (3H, d,J=6 Hz), 2.00–2.65 (2H, m), 3.60–4.35 (7H, m), 5.32 (1H, brs), 6.70–7.40(9H, m), 7.43 (1H, s), 7.64 (1H, s)

MS: 510 (M+H)⁺

EXAMPLE 65

This compound was prepared by a similar procedure to that of Example 16.

-   1-{(2S,3R)-2-hydroxy-5-[(3′-methoxy-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide    (65).

IR (KBr, cm⁻¹): 3600–2800, 1660, 1599, 1473, 1234, 1090

NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10–2.60 (2H, m), 3.55–4.30(7H, m), 5.19 (1H, d, J=5 Hz), 6.80–7.45 (10H, m), 7.71 (1H, s), 7.75(1H, S)

MS: 396 (M+H)⁺

Preparation 11

This compound was prepared by a similar procedure to that of Preparation5.

-   3-(2-Methoxy-5-pyridyl)phenol.

IR (KBr, cm⁻¹): 3600–2800, 1603, 1240, 1130, 1088, 1038, 791

NMR (CDCl₃, δ): 3.99 (3H, s), 5.41 (1H, s), 6.75–6.90 (2H, m), 7.01 (1H,t, J=2 Hz), 7.04–7.15 (1H, m), 7.31 (1H, t, J=8 Hz), 7.78 (1H, dd, J=8.2Hz), 8.39 (1H, d, J=2 Hz)

MS: 202 (M+H)⁺

EXAMPLE 66

This compound was prepared by a similar procedure to that of Example 15.

-   1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(2-methoxy-5-pyridyl)phenoxy]-3-pentyl}imidazole-4-carboxamide    (66).

IR (KBr, cm⁻¹): 3600–2800, 1666, 1602, 1284, 1257, 1099, 1027

NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.11 (3H, d,J=6 Hz), 2.00–2.65 (2H, m), 3.55–4.35 (7H, m), 5.33 (1H, brs), 6.70–7.40(6H, m), 7.43 (1H, s), 7.64 (1H, s), 7.75 (1H, dd, J=8,3 Hz), 8.35 (1H,d, J=3 Hz)

MS: 511 (M+H)⁺

EXAMPLE 67

This compound was prepared by a similar procedure to that of Example 16.

-   1-{(2S,3R)-2-hydroxy-5-[3-(2-methoxy-5-pyridyl)phenoxyl-3-pentyl}imidazole-4-carboxamide    (67).

IR (KBr, cm⁻¹): 3600–2800, 1660, 1602, 1479, 1282, 1242, 1092, 1024

NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10–2.60 (2H, m), 3.55–4.30(7H, m), 5.19 (1H, d, J=5 Hz), 6.75–7.40 (7H, m), 7.71 (1H, s), 7.75(1H, s), 7.99 (1H, dd, J=9.3 Hz), 8.46 (1H, d, J=3 Hz)

MS: 397 (M+H)⁺

EXAMPLE 68

This compound was prepared by a similar procedure to that of Example 15.

-   1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(6-phenyl-2-pyridyl)oxy]-3-pentyl}imidazole-4-carboxamide    (68).

NMR (CDCl₃, δ): 0.00 (3H, s), 0.04 (3H, s), 0.88 (9H, s) 1.07 (3H, d,J=6 Hz), 2.05–2.70 (2H, m), 3.90–4.60 (4H, m), 5.33 (1H, brs), 6.62 (1H,d, J=8 Hz), 6.91 (1H, brs), 7.25–7.50 (5H, m), 7.60 (1H, d, J=8 Hz),7.65 (1H, s), 7.88–8.00 (2H, m)

MS: 481 (M+H)⁺

EXAMPLE 69

This compound was prepared by a similar procedure to that of Example 16.

-   1-{(2S,3R)-2-hydroxy-5-[(6-phenyl-2-pyridyl)oxy]-3-pentyl}imidazole-4-carboxamide    (69).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1581, 1444, 1248, 1088

NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10–2.60 (2H, m) 3.75–4.45 (4H,m), 5.17 (1H, d, J=5 Hz), 6.71 (1H, d, J=8 Hz), 7.03 (1H, brs), 7.24(1H, brs), 7.32–7.60 (4H, m), 7.60 (1H, d, J=8 Hz), 7.65–8.10 (5H, m)

MS: 367 (M+H)⁺

EXAMPLE 70

This compound was prepared by a similar procedure to that of Example 15.

-   1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(4′-fluoro-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide    (70).

NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.11 (3H, d,J=6 Hz), 2.00–2.65 (2H, m), 3.60–4.35 (4H, m), 5.33 (1H, brs), 6.70–7.20(6H, m), 7.24–7.56 (4H, m), 7.64 (1H, s)

MS: 498 (M+H)⁺

EXAMPLE 71

This compound was prepared by a similar procedure to that of Example 16.

-   1-{(2S,3R)-5-[(4′-fluoro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide    (71).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1600, 1481, 1234, 1092

NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10–2.60 (2H, m) 3.55–4.30 (4H,m), 5.18 (1H, d, J=5 Hz), 6.75–7.40 (8H, m), 7.55–7.85 (4H, m)

MS: 384 (M+H)⁺

Preparation 12

This compound was prepared by a similar procedure to that of Preparation5.

-   4′-trifluoromethyl-1,1′-biphenyl-3-ol.

IR (KBr, cm⁻¹): 3600–2800, 1589, 1458, 1408, 1325, 1190, 1134, 1070,839, 781

NMR (CDCl₃, δ): 4.90 (1H, s), 6.80–6.95 (1H, m), 7.07 (1H, t, J=2 Hz),7.10–7.22 (1H, m), 7.34 (1H, t, J=8 Hz), 7.60–7.75 (4H, m)

MS: 237 (M−H)⁻

EXAMPLE 72

This compound was prepared by a similar procedure to that of Example 15.

-   1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-{[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl)oxy}-3-pentyl]imidazole-4-carboxamide    (72).

NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.91 (9H, s) 1.11 (3H, d,J=6 Hz), 2.10–2.60 (2H, m), 3.65–4.30 (4H, m), 5.33 (1H, brs), 6.82 (1H,m), 6.91 (1H, brs), 7.00 (1H, t, J=2 Hz), 7.17 (1H, m), 7.34 (1H, t, J=8Hz), 7.43 (1H, s), 7.62–7.72 (5H, m)

MS: 548 (M+H)⁺

EXAMPLE 73

This compound was prepared by a similar procedure to that of Example 16.

-   1-[(2S,3R)-2-hydroxy-5-{[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]oxy}-3-pentyl]imidazole-4-carboxamide    (73).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1599, 1328, 1165, 1119, 1070

NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.10–2.60 (2H, m), 3.60–4.35(4H, m), 5.18 (1H, d, J=5 Hz), 6.85–7.45 (6H, m), 7.63–8.00 (6H, m)

MS: 434 (M+H)⁺

Preparation 13

This compound was prepared by a similar procedure to that of Example 15.

-   Ethyl    1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(1H-pyrrol-1-yl)-2-naphthyloxy]-3-pentyl}imidazole-4-carboxylate.

NMR (CDCl₃, δ): −0.04 (3H, s), 0.03 (3H, s), 0.91 (9H, s), 1.08 (3H, d,J=6 Hz), 1.34 (3H, t, J=7 Hz), 2.00–2.65 (2H, m), 3.40–4.40 (6H, m),6.38 (2H, t, J=2 Hz) 7.06 (2H, t, J=2 Hz), 7.13 (2H, s), 7.30–7.55 (3H,m), 7.65–7.80 (3H, m)

MS: 548 (M+H)⁺

Preparation 14

This compound was prepared by a similar procedure to that of Example 16.

-   Ethyl    1-{(2S,3R)-2-hydroxy-5-[3-(1H-pyrrol-1-yl)-2-naphthyloxy]-3-pentyl}imidazole-4-carboxylate.

IR (KBr, cm⁻¹): 3600–2800, 1714, 1506, 1236, 1192, 1099

NMR (CDCl₃, δ): 1.14 (3H, d, J=6 Hz), 1.34 (3H, t, J=7 Hz), 2.05–2.65(2H, m), 2.81 (1H, br), 3.40–4.40 (6H, m), 6.39 (2H, t, J=2 Hz), 7.07(2H, t, J=2 Hz), 7.16 (2H, s), 7.30–7.60 (3H, m), 7.65–7.85 (3H, m)

MS: 434 (M+H)⁺

EXAMPLE 74

This compound was prepared by a similar procedure to that of Preparation1.

-   1-{(2S,3R)-2-hydroxy-5-[3-(1H-pyrrol-1-yl)-2-naphthyloxy]-3-pentyl}imidazole-4-carboxamide    (74).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1595, 1500, 1463, 1410, 1255, 1097

NMR (DMSO-d₆, δ): 0.92 (3H, d, J=6 Hz), 2.10–2.60 (2H, m), 3.50–4.25(4H, m), 5.18 (1H, d, J=5 Hz), 6.29 (2H, t, J=2 Hz), 7.02 (1H, brs),7.20 (2H, t, J=2 Hz), 7.24 (1H, brs), 7.35–7.55 (4H, m), 7.72 (1H, s),7.75–7.95 (3H, m)

MS: 405 (M+H)⁺

Preparation 15

This compound was prepared by a similar procedure to that of Preparation13.

-   Ethyl    1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(1-methyl-1H-indol-5-yloxy)-3-pentyl]imidazole-4-carboxylate.

NMR (CDCl₃, δ): 0.01 (3H, s), 0.06 (3H, s), 0.91 (9H, s), 1.13 (3H, d,J=6 Hz), 1.37 (3H, t, J=7 Hz), 2.00–2.60 (2H, m), 3.55–4.45 (9H, m),6.35 (1H, d, J=3 Hz), 6.78 (1H, dd, J=9.2 Hz), 6.97 (1H, d, J=2 Hz),7.01 (1H, d, J=3 Hz), 7.18 (1H, d, J=9 Hz), 7.52 (1H, s), 7.68 (1H, s)

MS: 486 (M+H)⁺

Preparation 16

This compound was prepared by a similar procedure to that of Example 16.

-   Ethyl    1-[(2S,3R)-2-hydroxy-5-(1-methyl-1H-indol-5-yloxy)-3-pentyl]imidazole-4-carboxylate.

IR (KBr, cm⁻¹): 3600–2800, 1699, 1313, 1234, 1147, 1026

NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 1.25 (3H, t, J=7 Hz), 2.10–2.55(2H, m), 3.45–4.35 (9H, m), 5.18 (1H, d, J=5 Hz), 6.26 (1H, d, J=3 Hz),6.72 (1H, dd, J=9.2 Hz), 6.94 (1H, d, J=2 Hz), 7.23 (1H, d, J=3 Hz),7.28 (1H, d, J=9 Hz), 7.77 (1H, s), 7.96 (1H, s)

MS: 372 (M+H)⁺

EXAMPLE 75

This compound was prepared by a similar procedure to that of Preparation1.

-   1-[(2S,3R)-2-hydroxy-5-(1-methyl-1H-indol-5-yloxy)-3-pentyl]imidazole-4-carboxamide    (75).

mp. 211–213.5° C.

IR (KBr, cm⁻¹): 3600–2800, 1666, 1583, 1495, 1398, 1242, 1151, 1103

NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.05–2.55 (2H, m) 3.45–4.35 (7H,m), 5.18 (1H, brs), 6.27 (1H, d, J=3 Hz), 6.73 (1H, dd, J=9.2 Hz), 6.94(1H, d, J=2 Hz), 7.01 (1H, brs), 7.15–7.35 (3H, m), 7.69 (1H, s), 7.74(1H, s)

MS: 343 (M+H)⁺

Preparation 17

To a stirred mixture of ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-hydroxy-3-pentyl]imidazole-4-carboxylate(500 mg, 1.4 mmol) and methanesulfonyl chloride (321 mg, 2.8 mmol) indichloromethane (15 ml) was added dropwise triethylamine (284 mg, 2.8mmol) at ice-bath temperature. After 1 h, the reaction mixture waspartitioned between dichloromethane and water. The organic layer waswashed with brine, dried (magnesium sulfate), and concentrated in vacuoto give ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-methanesulfonyloxy-3-pentyl]imidazole-4-carboxylate(642 mg, 105%) as a syrup. This material was used for the next reactionwithout further purification.

Preparation 18

To a mixture of ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-methanesulfonyloxy-3-pentyl]imidazole-4-carboxylate(160 mg, 0.368 mmol) and 2-naphthalenethiol (118 mg, 0.736 mmol) in DMF(5 ml) was added potassium carbonate (102 mg, 0.736 mmol) at roomtemperature and the reaction mixture was stirred for 2 hours. Theresulting reaction mixture was poured into water (25 ml) and extractedwith ethyl acetate. The organic layer was washed with brine, dried(sodium sulfate) and evaporated in vacuo. The residue was purified bysilica gel (10 g) chromatography eluting with chloroform/methanol (100:1to 50:1) to give ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(2-naphthylthio)-3-pentyl]imidazole-4-carboxylate(146 mg, 79.5%).

IR (neat, cm⁻¹): 3425, 2954, 2860, 1722, 1591, 1238, 1089

NMR (CDCl₃, δ): −0.08 (3H, s), −0.04 (3H, s), 0.78 (9H, s), 1.00 (3H, d,J=6 Hz), 1.39 (3H, t, J=7 Hz), 2.00–2.35 (2H, m), 2.65–3.10 (2H, m),3.75–4.25 (2H, m), 4.37 (2H, q, J=7 Hz), 7.30–7.55 (4H, m), 7.60 (1H,s), 7.65–7.85 (4H, m)

MS: 499 (M+H)⁺

Preparation 19

This compound was prepared by a similar procedure to that of Example 16.

-   Ethyl    1-[(2S,3R)-2-hydroxy-5-(2-naphthylthio)-3-pentyl]imidazole-4-carboxylate.

IR (neat, cm⁻¹): 3600–2800, 1720, 1226, 1193, 1126

NMR (DMSO-d₆, δ): 0.86 (3H, d, J=6 Hz), 1.27 (3H, t, J=7 Hz), 2.10–2.35(2H, m), 2.70–2.95 (2H, m), 3.70–4.30 (4H, m), 5.14 (1H, d, J=5 Hz),7.30–7.55 (3H, m), 7.62–7.80 (6H, m)

MS: 385 (M+H)⁺

EXAMPLE 76

This compound was prepared by a similar procedure to that of Preparation1.

-   1-[(2S,3R)-2-hydroxy-5-(2-naphthylthio)-3-pentyl]imidazole-4-carboxamide    (76).

IR (KBr, cm⁻¹): 3600–2800, 1657, 1591, 1413, 1261, 1240, 1126, 1097,1076

NMR (DMSO-d₆, δ): 0.87 (3H, d, J=6 Hz), 2.05–2.40 (2H, m) 2.65–3.00 (2H,m), 3.70–4.20 (2H, m), 5.13 (1H, d, J=5 Hz), 7.06 (1H, brs), 7.28 (1H,brs), 7.30–7.60 (3H, m), 7.62–7.95 (6H, m)

MS: 356 (M+H)⁺

Preparation 20

This compound was prepared by a similar procedure to that of Preparation18.

-   Ethyl    1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(1-naphthylthio)-3-pentyl]imidazole-4-carboxylate.

IR (neat, cm⁻¹): 3446, 2956, 2858, 1724, 1236, 1184, 1130

NMR (CDCl₃, δ): −0.09 (3H, s), −0.02 (3H, s), 0.82 (9H, s) 0.96 (3H, d,J=6 Hz), 1.39 (3H, t, J=7 Hz), 2.00–2.25 (2H, m), 2.45–3.05 (2H, m),3.75–4.20 (2H, m), 4.37 (2H, q, J=7 Hz), 7.30–7.62 (6H, m), 7.70–7.90(2H, m), 8.37 (1H, dd, J=9.2 Hz)

MS: 499 (M+H)⁺

Preparation 21

This compound was prepared by a similar procedure to that of Example 16.

-   Ethyl    1-[(2S,3R)-2-hydroxy-5-(1-naphthylthio)-3-pentyl]imidazole-4-carboxylate.

IR (neat, cm⁻¹): 3600–2800, 1720, 1223, 1196, 1126

NMR (DMSO-d₆, δ): 0.85 (3H, d, J=6 Hz), 1.27 (3H, t, J=7 Hz), 2.05–2.35(2H, m), 2.65–2.95 (2H, m), 3.65–4.30 (4H, m), 5.14 (1H, d, J=5 Hz),7.35–7.66 (4H, m), 7.72–8.03 (4H, m), 8.12–8.28 (1H, m)

MS: 385 (M+H)⁺

EXAMPLE 77

This compound was prepared by a similar procedure to that of Preparation1.

-   1-[(2S,3R)-2-hydroxy-5-(1-naphthylthio)-3-pentyl]imidazole-4-carboxamide    (77).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1593, 1413, 1336, 1261, 1128

NMR (DMSO-d₆, δ): 0.85 (3H, d, J=6 Hz), 2.05–2.35 (2H, m), 2.60–2.95(2H, m), 3.65–4.25 (2H, m), 5.12 (1H, d, J=5 Hz), 7.04 (1H, brs), 7.27(1H, brs), 7.35–8.03 (8H, m), 8.13–8.28 (1H, m)

MS: 356 (M+H)⁺

Preparation 22

This compound was prepared by a similar procedure to that of Preparation18.

-   Ethyl    1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(2-quinolylthio)-3-pentyl]imidazole-4-carboxylate.

IR (neat, cm⁻¹): 3450, 2954, 2858, 1722, 1238, 1182, 1136, 1091

NMR (CDCl₃, δ): −0.06 (3H, s), 0.00 (3H, s), 0.79 (9H, s), 1.04 (3H, d,J=6 Hz), 1.40 (3H, t, J=7 Hz), 2.20–2.60 (2H, m), 2.80–3.50 (2H, m),3.85–4.25 (2H, m), 4.38 (2H, q, J=7 Hz), 7.18 (1H, d, J=9 Hz), 7.35–7.80(5H, m), 7.84–8.00 (2H, m)

MS: 500 (M+H)⁺

Preparation 23

This compound was prepared by a similar procedure to that of Example 16.

-   Ethyl    1-[(2S,3R)-2-hydroxy-5-(2-quinolylthio)-3-pentyl]imidazole-4-carboxylate.

IR (neat, cm⁻¹): 3600–2800, 1718, 1230, 1193, 1132, 1092

NMR (DMSO-d₆, δ): 0.90 (3H, d, J=6 Hz), 1.28 (3H, t, J=7 Hz), 2.20–2.42(2H, m), 2.80–3.30 (2H, m), 3.70–4.35 (4H, m), 5.14 (1H, d, J=5 Hz),7.34 (1H, d, J=9 Hz), 7.40–7.95 (5H, m), 8.01 (1H, s), 8.14 (1H, d, J=9Hz)

MS: 386 (M+H)⁺

EXAMPLE 78

This compound was prepared by a similar procedure to that of Preparation1.

-   1-[(2S,3R)-2-hydroxy-5-(2-quinolylthio)-3-pentyl)imidazole-4-carboxamide    (78).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1593, 1556, 1414, 1261, 1138, 1090

NMR (DMSO-d₆, δ): 0.91 (3H, d, J=6 Hz), 2.20–2.42 (2H, m) 2.75–3.30 (2H,m), 3.70–4.25 (2H, m), 5.11 (1H, d, J=5 Hz), 7.08 (1H, brs), 7.31 (1H,brs), 7.33 (1H, d, J=9 Hz), 7.40–7.95 (6H, m), 8.14 (1H, d, J=9 Hz)

MS: 357 (M+H)⁺

Preparation 24

This compound was prepared by a similar procedure to that of Preparation18.

-   Ethyl    1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(3,4-dichlorophenylthio)-3-pentyl]imidazole-4-carboxylate.

IR (neat, cm⁻¹): 3446, 2956, 2858, 1724, 1236, 1184, 1130, 1105, 1027

NMR (CDCl₃, δ): −0.04 (3H, s), 0.02 (3H, s), 0.85 (9H, s) 1.03 (3H, d,J=6 Hz), 1.39 (3H, t, J=7 Hz), 1.95–2.35 (2H, m), 2.40–2.97 (2H, m),3.80–4.15 (2H, m), 4.37 (2H, q, J=7 Hz), 7.09 (1H, dd, J=8.2 Hz), 7.35(1H, d, J=8 Hz), 7.36 (1H, d, J=2 Hz), 7.50 (1H, s), 7.59 (1H, s)

MS: 517 (M+H)⁺ (³⁵Cl×2), 519 (M+H)⁺ (³⁵Cl−³⁷Cl)

Preparation 25

This compound was prepared by a similar procedure to that of Example 16.

-   Ethyl    1-[(2S,3R)-5-(3,4-dichlorophenylthio)-2-hydroxy-3-pentyl]imidazole-4-carboxylate.

IR (neat, cm⁻¹): 3600–2800, 1716, 1232, 1191, 1124, 1027

NMR (DMSO-d₆, δ): 0.85 (3H, d, J=6 Hz), 1.27 (3H, t, J=7 Hz), 2.05–2.30(2H, m), 2.65–2.90 (2H, m), 3.70–4.30 (4H, m), 5.14 (1H, d, J=5 Hz),7.24(1H, dd, J=8.2 Hz), 7.50 (1H, d, J=2 Hz), 7.53 (1H, d, J=8 Hz), 7.78(1H, s), 7.92 (1H, s)

MS: 403 (M+H)⁺ (³⁵Cl×2), 405 (M+H)⁺ (³⁵Cl−³⁷Cl)

EXAMPLE 79

This compound was prepared by a similar procedure to that of Preparation1.

-   1-[(2S,3R)-5-(3,4-dichlorophenylthio)-2-hydroxy-3-pentyl]imidazole-4-carboxamide    (79).

IR (KBr, cm⁻¹): 3600–2800, 1660, 1594, 1456, 1414, 1263, 1126, 1101

NMR (DMSO-d₆, δ): 0.86 (3H, d, J=6 Hz), 2.05–2.30 (2H, m) 2.65–2.90 (2H,m), 3.70–4.15 (2H, m), 5.13 (1H, d, J=5 Hz), 7.03 (1H, brs), 7.24 (1H,dd, J=8.2 Hz), 7.25 (1H, brs), 7.51 (1H, d, J=2 Hz), 7.53 (1H, d, J=8Hz), 7.70 (1H, s), 7.72 (1H, s)

MS: 374 (M+H)⁺ (³⁵Cl×2), 376 (M+H)⁺ (³⁵Cl−³⁷Cl)

Preparation 26

This compound was prepared by a similar procedure to that of Preparation18.

-   Ethyl    1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(3,4-dimethylphenylthio)-3-pentyl]imidazole-4-carboxylate.

IR (neat, cm⁻¹): 3448, 2954, 2858, 1724, 1234, 1184, 1130, 1105, 1025

NMR (CDCl₃, δ)s: −0.06 (3H, s), 0.01 (3H, s), 0.84 (9H, s), 1.01 (3H, d,J=6 Hz), 1.39 (3H, t, J=7 Hz), 1.95–2.30 (8H, m), 2.35–2.95 (2H, m),3.80–4.20 (2H, m), 4.37 (2H, q, J=7 Hz), 7.00–7.15 (1H, m), 7.44 (1H,s), 7.56 (1H, s)

MS: 477 (M+H)⁺

Preparation 27

This compound was prepared by a similar procedure to that of Example 16.

-   Ethyl    1-[(2S,3R)-5-(3,4-dimethylphenylthio)-2-hydroxy-3-pentyl]imidazole-4-carboxylate.

IR (neat, cm⁻¹): 3600–2800, 1716, 1230, 1192, 1124, 1027

NMR (DMSO-d₆, δ): 0.86 (3H, d, J=6 Hz), 1.27 (3H, t, J=7 Hz), 2.00–2.30(8H, m), 2.50–2.75 (2H, m), 3.65–4.30 (4H, m), 5.12 (1H, d, J=5 Hz),6.90–7.10 (3H, m), 7.75 (1H, s), 7.89 (1H, s)

MS: 363 (M+H)⁺

EXAMPLE 80

This compound was prepared by a similar procedure to that of Preparation1.

-   1-[(2S,3R)-5-(3,4-dimethylphenylthio)-2-hydroxy-3-pentyl]imidazole-4-carboxamide    (80).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1595, 1489, 1415, 1263, 1238, 1126,1093

NMR (DMSO-d₆, δ): 0.86 (3H, d, J=6 Hz), 2.00–2.25 (8H, m), 2.50–2.75(2H, m), 3.70–4.15 (2H, m), 5.10 (1H, d, J=5 Hz), 6.95–7.12 (4H, m),7.25 (1H, brs), 7.67 (2H, s)

MS: 334 (M+H)⁺

Preparation 28

To a suspension of (2R,3S)-2-amino-1,3-butanediol4-methylbenzenesulfonate (2.3 g) in nitromethane (32 mL) was addedtriethylamine (1.1 mL) and triethyl orthoformate (1.3 mL). The mixturewas stirred at 110° C. for 0.5 hour and cooled in an ice-bath. A mixtureof ethyl α-amino-α-cyanoacetate 4-methylbenzenesulfonate (2.0 g),triethylamine (1.0 mL) and acetonitrile (32 mL) was added to thereaction mixture, and the whole was stirred at 100° C. for 8 hours. Themixture was concentrated in vacuo and the residue was purified by columnchromatography on silica gel (gradient elution; 10:1 to 5:1chloroform-methanol containing 1% ammonium hydroxide) to give the crudeproduct, which was further purified by column chromatography on silicagel (gradient elution; 20:1 to 10:1 to 5:1 ethyl acetate-1% ammoniumhydroxide/methanol) to give ethyl5-amino-1-[(1R,2S)-2-hydroxy-1-(hydroxymethyl)propyl]-1H-imidazole-4-carboxylate(1.0 g).

NMR (DMSO-d₆); 0.93 (3H, d, J=6 Hz), 1.23 (3H, t, J=7 Hz), 3.8–4.1 (4H,m), 4.12 (2H, q, J=7 Hz), 4.9–5.0 (1H, m), 5.17 (1H, d, J=5 Hz), 5.89(2H, br s), 7.17 (1H, s)

Preparation 29

To a refluxing solution of isoamyl nitrite (1.5 mL) in tetrahydrofuran(4.6 mL) was added a solution of ethyl5-amino-1-[(1R,2S)-2-hydroxy-1-(hydroxymethyl)propyl]-1H-imidazole-4-carboxylate(0.92 g) in tetrahydrofuran (23 mL) dropwise over 45 minutes, and themixture was refluxed for 75 minutes. The reaction mixture was cooled toambient temperature and concentrated in vacuo. The residue was purifiedby column chromatography on silica gel (gradient elution; 10:1 to 5:1chloroform-1% ammonium hydroxide/methanol) to give ethyl1-[(1R,2S)-2-hydroxy-1-(hydroxymethyl)propyl]-1H-imidazole-4-carboxylate(0.50 g).

NMR (DMSO-d₆); 0.88 (3H, d, J=6 Hz), 1.26 (3H, t, J=7 Hz), 3.7–4.1 (4H,m), 4.21 (2H, q, J=7 Hz), 4.86 (1H, br s) 5.07 (1H, br s), 7.72 (1H, d,J=1 Hz), 7.88 (1H, d, J=1 Hz)

Preparation 30

A mixture of ethyl1-[(1R,2S)-2-hydroxy-1-(hydroxymethyl)propyl]-1H-imidazole-4-carboxylate(0.88 g), 4-chlorophenylsulfonyl chloride (1.2 g) and pyridine (8.8 mL)was stirred at 4° C. for 3 days. The mixture was poured into water, andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous sodium sulfate, and concentrated in vacuo. The residuewas purified by column chromatography on silica gel (gradient elution;50:1 to 25:1 chloroform-methanol) to give ethyl1-[(1R,2S)-1-({[4-chlorophenyl]sulfonyl}oxy)methyl)-2-hydroxypropyl]-1H-imidazole-4-carboxylate(0.89 g).

NMR (DMSO-d₆); 0.84 (3H, d, J=6 Hz), 1.27 (3H, t, J=7 Hz), 3.8–4.0 (1H,m), 4.21 (2H, q, J=7 Hz), 4.3–4.4 (1H, m), 4.54 (2H, d, J=6 Hz), 5.39(1H, d, J=5 Hz), 7.6–7.9 (6H, m)

Preparation 31

A mixture of 3,4-dichlorophenol (1.0 g), cesium carbonate (2.1 g) andN,N-dimethylformamide (6 mL) was stirred at 80° C. for an hour. To themixture was added a solution of ethyl1-[(1R,2S)-1-({[4-chlorophenyl]sulfonyl}oxy)methyl]-2-hydroxypropyl]-1H-imidazole-4-carboxylate(0.52 g) in N,N-dimethylformamide (6 mL). The reaction mixture wasstirred at 80° C. overnight, cooled to ambient temperature and dilutedwith ethyl acetate. The precipitate was filtered off and the filtratewas successively washed with 1 N sodium hydroxide, water and brine,dried over anhydrous sodium sulfate, and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel (elution;25:1 chloroform-methanol) to give the crude product, which was furtherpurified by recrystallization from 1:1 n-hexane-ethyl acetate (4 mL) togive ethyl1-{(1R,2S)-1-[(3,4-dichlorophenoxy)methyl]-2-hydroxypropyl}-1H-imidazole-4-carboxylate(0.25 g).

mp: 101–103° C.

NMR (DMSO-d₆); 0.96 (3H, d, J=6 Hz), 1.25 (3H, t, J=7 Hz), 4.0–4.1 (1H,m), 4.20 (2H, q, J=7 Hz), 4.4–4.6 (3H, m), 5.3–5.4 (1H, br m), 6.93 (1H,dd, J=2 Hz, 9 Hz), 7.24 (1H, d, J=2 Hz), 7.51 (1H, d, J=9 Hz), 7.87 (1H,d, J=1 Hz), 8.03 (1H, s)

EXAMPLE 81

A mixture of ethyl1-{(1R,2S)-1-[(3,4-dichlorophenoxy)methyl]-2-hydroxypropyl}-1H-imidazole-4-carboxylate(0.23 g), 28% ammonium hydroxide (12 mL) and 1,2-dimethoxyethane (6 mL)was heated at 100° C. in the stainless steel bottle for 24 hours. Aftercooling, the reaction mixture was concentrated in vacuo and the residuewas purified by column chromatography on silica gel (gradient elution;20:1 to 10:1 chloroform-methanol) to give the product, which wasrecrystallized from 1:5 n-hexane-ethyl acetate (12 mL) to give1-{(1R,2S)-1-[(3,4-dichlorophenoxy)methyl]-2-hydroxypropyl}-1H-imidazole-4-carboxamide(81) (0.13 g).

mp: 115–121° C.

APCIMS: 344, 346 (M+H)

IR (KBr): 3328, 1664 cm⁻¹

NMR (DMSO-d₆); 0.95 (3H, d, J=6 Hz), 3.9–4.1 (1H, m), 4.3–4.6 (3H, m),5.34 (1H, d, J=5 Hz), 6.94 (1H, dd, J=2 Hz, 9 Hz), 7.05 (1H, br, s),7.25 (1H, d, J=2 Hz), 7.26 (1H, br, s), 7.51 (1H, d, J=9 Hz), 7.79 (1H,s), 7.80 (1H, s)

Preparation 32

This compound was prepared by a similar procedure to that of Preparation5.

-   3′-hydroxy-1,1′-biphenyl-4-carbonitrile.

IR (KBr, cm⁻¹): 3500–2800, 2231, 1591, 1477, 1303, 1203, 839, 779

NMR (CDCl₃, δ): 5.10 (1H, s), 6.80–7.40 (4H, m), 7.55–7.80 (4H, m)

MS: 218 (M+Na)⁺

EXAMPLE 82

This compound was prepared by a similar procedure to that of Example 15.

-   1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(4′-cyano-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide    (82).

NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.11 (3H, d,J=6 Hz), 2.05–2.70 (2H, m), 3.60–4.35 (4H, m), 5.38 (1H, brs), 6.75–7.00(3H, m), 7.10–7.45 (3H, m), 7.55–7.80 (5H, m)

MS: 505 (M+H)⁺

EXAMPLE 83

This compound was prepared by a similar procedure to that of Example 16.

-   1-{(2S,3R)-5-[(4′-cyano-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide    (83).

IR (KBr, cm⁻¹): 3600–2800, 2240, 1658, 1595, 1209, 839

NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.10–2.60 (2H, m) 3.60–4.30 (4H,m), 5.19 (1H, d, J=5 Hz), 6.85–7.45 (6H, m), 7.60–8.00 (6H, m)

MS: 391 (M+H)⁺

Preparation 33

This compound was prepared by a similar procedure to that of Preparation5.

-   4′-methyl-1,1′-biphenyl-3-ol.

IR (KBr, cm⁻¹): 3600–2800, 1595, 1481, 1296, 1192, 879, 775

NMR (CDCl_(3, δ):) 2.39 (3H, s), 4.83 (1H, s), 6.70–6.90 (1H, m),6.95–7.55 (7H, m)

MS: 183 (M−H)⁻

EXAMPLE 84

This compound was prepared by a similar procedure to that of Example 15.

-   1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(4′-methyl-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide    (84).

NMR (CDCl₃, δ): 0.02 (3H, s), 0.06 (3H, s), 0.91 (9H, s) 1.10 (3H, d,J=6 Hz), 2.00–2.65 (5H, m), 3.55–4.35 (4H, m), 5.32 (1H, brs), 6.70–7.50(10H, m), 7.64 (1H, s)

MS: 494 (M+H)⁺

EXAMPLE 85

This compound was prepared by a similar procedure to that of Example 16.

-   1-{(2S,3R)-2-hydroxy-5-[(4′-methyl-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide    (85).

IR (KBr, cm⁻¹): 3600–2800, 1658, 1595, 1479, 1410, 1263, 1090, 781

NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.10–2.60 (5H, m) 3.55–4.35 (4H,m), 5.19 (1H, brs), 6.70–7.40 (8H, m), 7.57 (2H, d, J=8 Hz), 7.71 (1H,s), 7.76 (1H, s)

MS: 380 (M+H)⁺

Preparation 34

This compound was prepared by a similar procedure to that of Preparation5.

-   3-(6-chloro-3-pyridyl)phenol.

IR (KBr, cm⁻¹): 3500–2700, 1599, 1454, 1238, 1111

NMR (CDCl₃, δ): 5.85 (1H, s), 6.80–7.15 (3H, m), 7.25–7.50 (2H, m), 7.84(1H, dd, J=8,3 Hz), 8.62 (1H, d, J=3 Hz)

MS: 204 (M−H)⁻ (³⁵Cl), 206 (M−H)⁻ (³⁷Cl)

EXAMPLE 86

This compound was prepared by a similar procedure to that of Example 15.

-   1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(6-chloro-3-pyridyl)phenoxy]-3-pentyl}imidazole-4-carboxamide    (86).

NMR (CDCl₃, δ): 0.02 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.10 (3H, d,J=6 Hz), 2.05–2.70 (2H, m), 3.60–4.35 (4H, m), 5.35 (1H, brs), 6.75–7.00(3H, m), 7.11 (1H, d, J=8 Hz), 7.25–7.50 (3H, m), 7.64 (1H, s), 7.80(1H, dd, J=8, 2 Hz), 8.56 (1H, d, J=2 Hz)

MS: 515 (M+H)⁺ (³⁵Cl), 517 (M+H)⁺ (³⁷Cl)

EXAMPLE 87

This compound was prepared by a similar procedure to that of Example 16.

-   1-{(2S,3R)-5-[3-(6-chloro-3-pyridyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide    (87).

mp. 166–168° C.

IR (KBr, cm⁻¹): 3600–2800, 1652, 1592, 1456, 1236, 1105

NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10–2.60 (2H, m) 3.55–4.35 (4H,m), 5.19 (1H, d, J=5 Hz), 6.93 (1H, dd, J=8, 1 Hz), 7.03 (1H, brs),7.10–7.45 (4H, m), 7.59 (1H, d, J=8 Hz), 7.71 (1H, s), 7.75 (1H, s),8.14 (1H, dd, J=8, 2 Hz), 8.72 (1H, d, J=2 Hz)

MS: 401 (M+H)⁺ (³⁵Cl), 403 (M+H)⁺ (³⁷Cl)

Preparation 35

This compound was prepared by a similar procedure to that of Preparation5.

-   2-(4-chlorophenyl)-6-methoxypyridine.

IR (KBr, cm⁻¹): 2976, 2943, 1579, 1464, 1254, 1020, 793

NMR (CDCl₃, δ): 4.03 (3H, s), 6.70 (1H, d, J=8 Hz), 7.20–7.70 (4H, m),7.90–8.05 (2H, m)

MS: 220 (M+H)⁺ (³⁵Cl), 222 (M+H)⁺ (³⁷Cl)

Preparation 36

To a stirred solution of 2-(4-chlorophenyl)-6-methoxypyridine (450 mg,2.05 mmol) in chlorobenzene (5 ml) was added AlCl₃ (1.09 g, 8.19 mmol)at room temperature. The resulting mixture was stirred under reflux for10 min. The mixture was quenched with crushed ice under ice bathtemperature and partitioned between ethyl acetate (20 ml) and HClaq. Theorganic layer was washed with water and brine, dried (magnesium sulfate)and evaporated in vacuo.

The residue was triturated with hexane and dried under reduced pressureto give 6-(4-chlorophenyl)-2(1H)-pyridinone (382 mg, 91%) as a whitesolid.

IR (KBr, cm⁻¹): 3600–2600, 1672, 1616, 1491, 1090, 791

NMR (DMSO-d₆, δ): 6.35–6.70 (2H, m), 7.35–7.75 (5H, m), 11.65 (1H, br)

MS: 228 (M+Na)⁺ (³⁵Cl), 230 (M+Na)⁺ (³⁷Cl)

EXAMPLE 88

This compound was prepared by a similar procedure to that of Example 15.

-   1-((2S,3R)-2-(tert-butyldimethylsilyloxy)-5-{[6-(4-chlorophenyl)-2-pyridyl]oxy}-3-pentyl)imidazole-4-carboxamide    (88).

NMR (CDCl₃, δ): 0.02 (3H, s), 0.04 (3H, s), 0.88 (9H, s), 1.07 (3H, d,J=6 Hz), 2.05–2.70 (2H, m), 3.85–4.65 (4H, m), 5.38 (1H, brs), 6.64 (1H,d, J=8 Hz), 6.93 (1H, brs), 7.20–7.75 (6H, m), 7.87 (2H, d, J=8 Hz)

MS: 515 (M+H)⁺ (³⁵Cl), 517 (M+H)⁺ (³⁷Cl)

EXAMPLE 89

This compound was prepared by a similar procedure to that of Example 16.

-   1-((2S,3R)-2-hydroxy-5-{[6-(4-chlorophenyl)-2-pyridyl]oxy}-3-pentyl)imidazole-4-carboxamide    (89).

IR (KBr, cm⁻¹): 3600–2800, 1662, 1591, 1444, 1251, 1092, 1020, 800

NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10–2.60 (2H, m), 3.75–4.45(4H, m), 5.18 (1H, d, J=5 Hz), 6.73 (1H, d, J=8 Hz), 7.06 (1H, brs),7.27 (1H, brs), 7.45–7.90 (6H, m), 8.01 (2H, d, J=9 Hz)

MS: 401 (M+H)⁺ (³⁵Cl), 403 (M+H)⁺ (³⁷Cl)

EXAMPLE 90

This compound was prepared by a similar procedure to that of Example 15.

-   1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(3′,5′-dichloro-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide    (90).

NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.11 (3H, d,J=6 Hz), 2.05–2.65 (2H, m), 3.60–4.35 (4H, m), 5.35 (1H, brs), 6.70–7.00(3H, m), 7.10 (1H, d, J=8 Hz), 7.25–7.50 (5H, m), 7.64 (1H, s)

EXAMPLE 91

This compound was prepared by a similar procedure to that of Example 16.

-   1-{(2S,3R)-5-[(3′,5′-dichloro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide    (91).

IR (KBr, cm⁻¹): 3600–2800, 1657, 1591, 1558, 1236, 1092, 850, 795

NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10–2.60 (2H, m), 3.50–4.35(4H, m), 5.19 (1H, d, J=5 Hz), 6.92 (1H, d, J=8, 1 Hz), 7.02 (1H, brs),7.15–7.45 (4H, m), 7.50–7.80 (5H, m)

MS: 434 (M+H)⁺ (³⁵Cl), 436 (M+H)⁺ (³⁷Cl)

EXAMPLE 92

This compound was prepared by a similar procedure to that of Example 15.

-   1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(7-methoxy-2-naphthyloxy)-3-pentyl]imidazole-4-carboxamide    (92).

NMR (CDCl₃, δ): 0.03 (3H, s), 0.06 (3H, s), 0.91 (9H, s), 1.11 (3H, d,J=6 Hz), 2.10–2.65 (2H, m), 3.65–4.35 (7H, m), 5.34 (1H, brs), 6.80–7.05(5H, m), 7.44 (1H, s), 7.55–7.70 (3H, m)

MS: 484 (M+H)⁺

EXAMPLE 93

This compound was prepared by a similar procedure to that of Example 16.

-   1-[(2S,3R)-2-hydroxy-5-(7-methoxy-2-naphthyloxy)-3-pentyl]imidazole-4-carboxamide    (93).

IR (KBr, cm⁻¹): 3600–2800, 1633, 1259, 1219, 1157, 1029, 835

NMR (DMSO-d₆, δ): 0.95 (3H, d, J=6 Hz), 2.10–2.60 (2H, m), 3.60–4.35(7H, m), 5.20 (1H, d, J=5 Hz), 6.80–7.35 (6H, m), 6.60–7.85 (4H, m)

MS: 370 (M+H)⁺

EXAMPLE 94

This compound was prepared by a similar procedure to that of Example 15.

-   1-[(2S,3R)-5-(7-bromo-2-naphthyloxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide    (94).

NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.11 (3H, d,J=6 Hz), 2.05–2.75 (2H, m), 3.60–4.35 (4H, m), 5.34 (1H, brs), 6.89 (1H,d, J=2 Hz), 6.90 (1H, brs), 7.07 (1H, dd, J=9.2 Hz), 7.34–7.75 (5H, m),7.83 (1H, s)

MS: 532 (M+H)⁺ (⁷⁹Br), 534 (M+H)⁺ (⁸¹Br)

EXAMPLE 95

This compound was prepared by a similar procedure to that of Example 16.

-   1-](2S,3R)-5-(7-bromo-2-naphthyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide    (95).

IR (KBr, cm⁻¹): 3600–2800, 1682, 1649, 1244, 1128, 1087, 837

(DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.10–2.65 (2H, m), 3.60–4.35 (4H,m), 5.20 (1H, d, J=5 Hz), 7.02 (1H, brs), 7.08–7.35 (3H, m), 7.43 (1H,dd, J=8.2 Hz), 7.60–7.90 (4H, m), 8.02 (1H, d, J=2 Hz)

MS: 418 (M+H)⁺ (⁷⁹Br)

EXAMPLE 96

This compound was prepared by a similar procedure to that of Example 15.

-   1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(7-chloro-2-naphthyloxy)-3-pentyl]imidazole-4-carboxamide    (96).

IR (KBr, cm⁻¹): 3600–2800, 1664, 1250, 1092, 835

NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.11 (3H, d,J=6 Hz), 2.05–2.70 (2H, m), 3.60–4.35 (4H, m), 5.36 (1H, brs), 6.89 (1H,d, J=2 Hz), 6.90 (1H, brs), 7.06 (1H, dd, J=9, 2 Hz), 7.15–7.35 (1H, m),7.43 (1H, s), 7.55–7.75 (4H, m)

MS: 488 (M+H)⁺ (³⁵Cl), 490 (M+H)⁺ (³⁷Cl)

EXAMPLE 97

This compound was prepared by a similar procedure to that of Example 16.

-   1-[(2S,3R)-5-(7-chloro-2-naphthyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide    (97).

mp. 139–141° C.

IR (KBr, cm⁻¹): 3600–2800, 1662, 1620, 1246, 1211, 1082, 839

NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.10–2.65 (2H, m), 3.60–4.35(4H, m), 5.20 (1H, d, J=5 Hz), 6.90–7.40 (5H, m), 7.60–7.95 (5H, m)

MS: 374 (M+H)⁺ (³⁵Cl), 376 (M+H)⁺ (³⁷Cl)

EXAMPLE 98

This compound was prepared by a similar procedure to that of Example 15.

-   1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(7-cyano-2-naphthyloxy)-3-pentyl]imidazole-4-carboxamide    (98).

NMR (CDCl₃, δ): 0.04 (3H, s), 0.08 (3H, s), 0.92 (9H, s), 1.12 (3H, d,J=6 Hz), 2.05–2.75 (2H, m), 3.60–4.35 (4H, m), 5.37 (1H, brs), 6.91 (1H,brs), 7.01 (1H, d, J=2 Hz), 7.22 (1H, dd, J=9.2 Hz), 7.45 (1H, s), 7.47(1H, d, J=9 Hz), 7.65 (1H, s), 7.74 (1H, d, J=9 Hz), 7.82 (1H, d, J=9Hz), 8.04 (1H, s)

MS: 479 (M+H)⁺

EXAMPLE 99

This compound was prepared by a similar procedure to that of Example 16.

-   1-[(2S,3R)-5-(7-cyano-2-naphthyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide    (99).

IR (KBr, cm⁻¹): 3600–2800, 2225, 1658, 1599, 1263, 1217, 1126, 1092, 842

NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.10–2.65 (2H, m), 3.60–4.35(4H, m), 5.20 (1H, brs), 7.05 (1H, brs), 7.15–7.45 (3H, m), 7.60 (1H,dd, J=8,1 Hz), 7.70–8.10 (4H, m), 8.36 (1H, s)

MS: 365 (M+H)⁺

EXAMPLE 100

This compound was prepared by a similar procedure to that of Example 15.

-   1-((2S,3R)-2-(tert-butyldimethylsilyloxy)-5-{[2-(4-chlorophenyl)-1,3-benzoxazol-6-yl]oxy}-3-pentyl)imidazole-4-carboxamide    (100).

IR (KBr, cm⁻¹): 3600–2800, 1666, 1592, 1481, 1261, 1145, 1095, 835

NMR (CDCl₃, δ): 0.04 (3H, s), 0.07 (3H, s), 0.92 (9H, s), 1.12 (3H, d,J=6 Hz), 2.05–2.70 (2H, m), 3.60–4.35 (4H, m), 5.35 (1H, brs), 6.80–7.05(3H, m), 7.35–7.70 (5H, m), 8.12 (2H, d, J=9 Hz)

MS: 555 (M+H)⁺ (³⁵Cl), 557 (M+H)⁺ (³⁷Cl)

EXAMPLE 101

This compound was prepared by a similar procedure to that of Example 16.

-   1-((2S,3R)-5-{[2-(4-chlorophenyl)-1,3-benzoxazol-6-yl]oxy}-2-hydroxy-3-pentyl)imidazole-4-carboxamide    (101).

IR (KBr, cm⁻¹): 3600–2800, 1654, 1617, 1481, 1267, 1146, 1053, 827

NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.10–2.70 (2H, m), 3.60–4.35(4H, m), 5.20 (1H, d, J=5 Hz), 6.80–7.45 (4H, m), 7.50–7.90 (5H, m),8.12 (2H, d, J=8 Hz)

MS: 441 (M+H)⁺ (³⁵Cl), 443 (M+H)⁺ (³⁷Cl)

REFERENCE EXAMPLE 1

Under N₂, a cold (−75° C.) solution of oxalyl chloride (285 mg, 2.24mmol) in CH₂Cl₂ (10 ml) was treated with DMSO (0.215 ml, 3.03 mmol) andstirred for 10 min. A solution of ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-hydroxy-3-pentyl]imidazole-4-carboxylate(400 mg, 1.12 mmol) in CH₂Cl₂ (5 ml) was slowly added, the resultingmixture was stirred for 50 min at −75 to −45° C. and finally treatedwith triethylamine (0.59 ml). The reaction mixture was allowed to warmto 0° C., hydrolyzed with water (10 ml) and extracted with CH₂Cl₂ (20ml×2). The combined organic layers were dried over sodium sulfate andevaporated in vacuo. The residue was purified by silica gel (13 g)chromatography eluting with chloroform/methanol (100:1) to give ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-oxo-3-pentyl]imidazole-4-carboxylate(370 mg, 93%) as a colorless syrup.

IR (neat, cm⁻¹): 3435, 2958, 2860, 1722, 1709, 1547, 1238, 1092, 1034

NMR (CDCl_(3, δ): −)0.01 (3H, s), 0.04 (3H, s), 0.91 (9H, s), 1.09 (3H,d, J=6 Hz), 1.38 (3H, t, J=7 Hz), 3.00–3.13 (1H, m), 3.85–4.60 (5H, m),7.56 (1H, s), 7.64 (1H, s)

MS: 377 (M+Na)⁺

REFERENCE EXAMPLE 2

Under N₂, to a suspension of 2-naphthylmethyltriphenylphosphoniumbromide (355 mg, 0.733 mmol) in THF (8 ml) and DMSO (4 ml) was addedt-BuOK at room temperature. After stirring for 20 min., the mixture wascooled to 5–7° C. in an ice bath and then ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-oxo-3-pentyl]imidazole-4-carboxylate(130 mg, 0.367 mmol) in THF (6 ml) was added. The mixture was stirredfor 1 h at room temperature. The reaction mixture was poured into water(25 ml) and extracted with ethyl acetate. The organic layer was washedwith brine, dried (sodium sulfate) and evaporated in vacuo. The residuewas purified by silica gel (15 g) chromatography eluting withchloroform/methanol (100:1 to 50:1) to give ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-6-(2-naphthyl)-5-hexen-3-yl]]imidazole-4-carboxylate(130 mg, 74.1%).

NMR (CDCl₃, δ): −0.03–0.08 (6H, m), 0.70–1.45 (15H, s), 2.60–3.20 (2H,m), 3.80–4.40 (4H, m), 5.35–6.75 (2H, m), 7.20–7.90 (9H, m)

MS: 479 (M+H)⁺

REFERENCE EXAMPLE 3

This compound was prepared by a similar procedure to that of Preparation3.

-   Ethyl    1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-6-(2-naphthyl)-3-hexyl]imidazole-4-carboxylate.

IR (neat, cm⁻¹): 3375, 2941, 2860, 1724, 1232, 1182, 1124, 1031

NMR (CDCl₃, δ): −0.05 (3H, s), 0.00 (3H, s), 0.83 (9H, s), 0.97 (3H, d,J=6 Hz), 1.39 (3H, t, J=7 Hz), 1.60–2.15 (4H, m), 2.77 (2H, t, J=7 Hz),3.75–4.00 (2H, m), 4.36 (2H, q, J=7 Hz), 7.15–7.60 (6H, m), 7.70–7.87(3H, m)

MS: 481 (M+H)⁺

REFERENCE EXAMPLE 4

This compound was prepared by a similar procedure to that of Example 16.

-   Ethyl    1-[(2S,3R)-2-hydroxy-6-(2-naphthyl)-3-hexyl]imidazole-4-carboxylate.

IR (neat, cm⁻¹): 3600–2800, 1718, 1234, 1188, 1124, 1028

NMR (DMSO-d₆, δ): 0.87 (3H, d, J=6 Hz), 1.15–1.65 (5H, m), 1.70–2.10(2H, m), 2.60–2.85 (2H, m), 3.65–4.10 (2H, m), 4.20 (2H, q, J=7 Hz),5.07 (1H, d, J=5 Hz), 7.20–7.50 (3H, m), 7.61 (1H, s), 7.70–7.95 (5H, m)

MS: 367 (M+H)⁺

REFERENCE EXAMPLE 5

This compound was prepared by a similar procedure to that of Preparation1.

-   1-[(2S,3R)-2-hydroxy-6-(2-naphthyl)-3-hexyl]imidazole-4-carboxamide.

IR (KBr, cm⁻¹): 3600–2800, 1658, 1593, 1412, 1261, 1240, 1124, 1093

NMR (DMSO-d₆, δ): 0.87 (3H, d, J=6 Hz), 1.15–1.60 (2H, m), 1.70–2.10(2H, m), 2.55–2.85 (2H, m), 3.65–4.10 (2H, m), 5.06 (1H, d, J=5 Hz),7.02 (1H, brs), 7.24 (1H, brs), 7.31 (1H, d, J=8 Hz), 7.35–7.90 (8H, m)

MS: 338 (M+H)⁺

REFERENCE EXAMPLE 6

A mixture of 2-naphthol (1.4 g), cesium carbonate (3.2 g) andN,N-dimethylformamide (10 mL) was stirred at 60° C. for half an hour. Tothe mixture was added a solution of ethyl1-[(1R,2S)-1-({[4-chlorophenyl]sulfonyl]oxy}methyl]-2-hydroxypropyl]-1H-imidazole-4-carboxylate(0.81 g) in N,N-dimethylformamide (10 mL). The reaction mixture wasstirred at 60° C. for 4 hours, cooled to ambient temperature and dilutedwith ethyl acetate. The precipitate was filtered off and the filtratewas succesively washed with 1 N sodium hydroxide, water and brine, driedover anhydrous sodium sulfate, and concentrated in vacuo. The residuewas purified by column chromatography on silica gel (elution; 25:1chloroform-methanol) to give the crude product, which was furtherpurified by recrystallization from ethanol to give ethyl1-{(1R,2S)-2-hydroxy-1-[(2-naphthyloxy)methyl]propyl}-1H-imidazole-4-carboxylate(0.13 g).

The mother liquor and the mixed fractions were combined and purified bycolumn chromatography on silica gel (gradient elution; 50:1 to 25:1chloroform-methanol) to give the additional product (0.14 g).

mp: 191–192° C.

NMR (DMSO-d₆); 1.00 (3H, d, J=6 Hz), 1.25 (3H, t, J=7 Hz), 4.0–4.1 (1H,m), 4.20 (2H, q, J=7 Hz), 4.4–4.7 (3H, m), 5.39 (1H, d, J=5 Hz), 7.0–7.2(1H, m), 7.3–7.5 (3H, m), 7.7–7.9 (3H, m), 7.91 (1H, d, J=1 Hz), 8.08(1H, d, J=1 Hz)

REFERENCE EXAMPLE 7

A mixture of ethyl1-{(1R,2S)-2-hydroxy-1-[(2-naphthyloxy)methyl]propyl}-1H-imidazole-4-carboxylate(0.25 g), 28% ammonium hydroxide (14 mL) and 1,2-dimethoxyethane (7 mL)was heated at 100° C. in the stainless steel bottle for 24 hours. Aftercooling, the reaction mixture was concentrated in vacuo and the residuewas purified by column chromatography on silica gel (gradient elution;20:1 to 10:1 chloroform-methanol) to give the product, which wasrecrystallized from 5:1 ethyl acetate-ethanol (6 mL) to give ethyl1-{(1R,2S)-2-hydroxy-1-[(2-naphthyloxy)methyl)propyl}-1H-imidazole-4-carboxamide(0.12 g).

mp: 162–164° C.

APCIMS: 326 (M+H)

IR (KBr): 3318, 1666 cm⁻¹

NMR (DMSO-d₆); 1.00 (3H, d, J=6 Hz), 3.9–4.2 (1H, m), 4.4–4.7 (3H, m),5.38 (1H, d, J=5 Hz), 7.0–7.2 (1H, m), 7.06 (1H, br, s), 7.2–7.5 (4H,m), 7.28 (1H, br, s), 7.7–7.9 (4H, m)

Preparation 37

To a mixture of ethyl1-[(1R,2S)-1-({[4-chlorophenyl]sulfonyl)}oxy)methyl]-2-hydroxypropyl]-1H-imidazole-4-carboxylate(0.32 g), 2-naphthalenethiol (0.19 g) and N,N-dimethylformamide (5 mL)was added cesium carbonate (0.38 g) and the reaction mixture was stirredat ambient temperature overnight. The mixture was partitioned betweenethyl acetate and water. The organic layer was separated, washed withbrine, dry over Na₂SO₄, and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (elution; 25:1chloroform-methanol) to give the product, which was triturated with 1:1n-hexane-ethyl acetate (10 mL) to give ethyl1-{(1R,2S)-2-hydroxy-1-[(2-naphthylthio)methyl]propyl}-1H-imidazole-4-carboxylate(0.19 g).

mp: 117–120° C.

NMR (DMSO-d₆); 0.92 (3H, d, J=6 Hz), 1.24 (3H, t, J=7 Hz), 3.5–4.1 (3H,m), 4.1–4.3 (1H, m), 4.17 (2H, q, J=7 Hz), 5.35 (1H, d, J=5 Hz), 7.3–7.6(3H, m), 7.7–7.9 (5H, m), 7.98 (1H, s)

EXAMPLE 102

A mixture of ethyl1-{(1R,2S)-2-hydroxy-1-[(2-naphthylthio)methyl]propyl}-1H-imidazole-4-carboxylate(0.18 g), 28% ammonium hydroxide (20 mL) and 1,2-dimethoxyethane (10 mL)was heated at 100° C. in the stainless steel bottle for 24 hours. Aftercooling, the reaction mixture was concentrated in vacuo and the residuewas purified by column chromatography on silica gel (elution; 10:1chloroform-1% ammonium hydroxide/methanol) to give the product, whichwas recrystallized from 3:7 n-hexane-ethyl acetate (10 mL) to give1-{(1R,2S)-2-hydroxy-1-[(2-naphthylthio)methyl]propyl}-1H-imidazole-4-carboxamide(102) (90 mg).

mp: >108° C. (dec.)

APCIMS: 342 (M+H)

NMR (DMSO-d₆); 0.92 (3H, d, J=6 Hz), 3.4–4.2 (4H, m), 5.34 (1H, d, J=5Hz), 7.05 (1H, br, s), 7.26 (1H, br, s), 7.4–7.6 (3H, m), 7.71 (1H, s),7.7–7.9 (5H, m)

Preparation 38

A mixture of ethyl1-[(1R,2S)-1-({[4-chlorophenyl]sulfonyl}oxy)methyl)-2-hydroxypropyl]-1H-imidazole-4-carboxylate(0.25 g), 1-naphthalenethiol (0.14 g), cesium carbonate (0.30 g) andN,N-dimethylformamide (5 mL) was stirred at ambient temperature for 1.5hours. The mixture was partitioned between ethyl acetate and water. Theorganic layer was separated, washed with brine, dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (gradient elution; 50:1 to 25:1 chloroform-methanol) togive the product, which was triturated with 10:1 diisopropylether-ethanol (11 mL) to give ethyl1-{(1R,2S)-2-hydroxy-1-[(1-naphthylthio)methyl]propyl}-1H-imidazole-4-carboxylate(0.19 g).

mp: 110–115° C.

NMR (DMSO-d₆); 0.87 (3H, d, J=6 Hz), 1.26 (3H, t, J=7 Hz), 3.5–4.0 (3H,m), 4.0–4.3 (1H, m), 4.20 (2H, q, J=7 Hz), 5.31 (1H, d, J=5 Hz), 7.4–7.6(4H, m), 7.78 (1H, s), 7.8–7.9 (1H, m), 7.9–8.2 (2H, m), 7.97 (1H, d,J=1 Hz)

EXAMPLE 103

A mixture of ethyl1-{(1R,2S)-2-hydroxy-1-[(1-naphthylthio)methyl]propyl}-1H-imidazole-4-carboxylate(0.18 g), 28% ammonium hydroxide (5 mL) and 1,2-dimethoxyethane (10 mL)was heated at 100° C. in the stainless steel bottle for 24 hours. Aftercooling, the reaction mixture was concentrated in vacuo and the residuewas purified by column chromatography on silica gel (gradient elution;15:1 to 10:1 chloroform-methanol) to give1-[(2R,3S)-1-(1-naphthylthio)-3-hydroxy-2-butyl]imidazol-4-carboxamide.The product was dissolved in MeOH (5 mL) and treated with a solution of4 N hydrogen chloride in ethyl acetate (1 mL). The mixture wasconcentrated in vacuo and the residue was recrystallized from 5:1 ethylacetate-methanol (6 mL) to give1-{(1R,2S)-2-hydroxy-1-[(1-naphthylthio)methyl]propyl}-1H-imidazole-4-carboxamidehydrochloride (103) (0.11 g).

mp: >168° C. (dec.)

MS: 342 (M (free)+H), 364 (M (free)+Na)

NMR (DMSO-d₆); 1.00 (3H, d, J=6 Hz), 3.3–4.0 (2H, m), 4.0–4.1 (1H, m),4.3–4.5 (1H, m), 4.8–6.6 (1H, br m), 7.4–7.7 (5H, m), 7.82 (1H, br, s),7.8–8.2 (3H, m), 8.20 (1H, br, s), 8.29 (1H, d, J=1 Hz), 9.09 (1H, s)

Preparation 39

A mixture of ethyl1-[(1R,2S)-1-({[4-chlorophenyl]sulfonyl}oxy)methyl]-2-hydroxypropyl]-1H-imidazole-4-carboxylate(0.30 g), 2,3-dichlorobenzenethiol (0.19 g), cesium carbonate (0.36 g)and N,N-dimethylformamide (5 mL) was stirred at ambient temperature for2 hours. The mixture was partitioned between ethyl acetate and water.The organic layer was separated, washed with brine, dried over Na₂SO₄,and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (gradient elution; 50:1 to 25:1chloroform-methanol) to give the product, which was triturated with 1:1diisopropyl ether-ethyl acetate (10 mL) to give ethyl1-{(1R,2S)-1-{[(2,3-dichlorophenyl)thio]methyl}-2-hydroxypropyl}-1H-imidazole-4-carboxylate(0.18 g).

mp: 141–143° C.

NMR (DMSO-d₆); 0.92 (3H, d, J=6 Hz), 1.26 (3H, t, J=7 Hz), 3.5–4.3 (4H,m), 4.20 (2H, q, J=7 Hz), 5.43 (1H, d, J=5 Hz), 7.3–7.5 (3H, m), 7.81(1H, s), 8.01 (1H, d, J=1 Hz)

EXAMPLE 104

A mixture of ethyl1-{(1R,2S)-1-{[(2,3-dichlorophenyl)thio]methyl}-2-hydroxypropyl}-1H-imidazole-4-carboxylate(0.17 g), 28% ammonium hydroxide (10 mL) and 1,2-dimethoxyethane (20 mL)was heated at 100° C. in the stainless steel bottle for 24 hours. Aftercooling, the reaction mixture was concentrated in vacuo and the residuewas purified by column chromatography on silica gel (elution; 10:1chloroform-1% ammonium hydroxide/methanol) to give the product, whichwas recrystallized from 1:1 n-hexane-ethyl acetate (10 mL) to give1-{(1R,2S)-1-{[(2,3-dichlorophenyl)thio]methyl}-2-hydroxypropyl}-1H-imidazole-4-carboxamide(104) (0.10 g).

mp: >120° C. (dec.)

APCIMS: 359, 361 (M+H)

IR (KBr): 3322, 1662 cm⁻¹

NMR (DMSO-d₆); 0.92 (3H, d, J=6 Hz), 3.4–4.2 (4H, m), 5.42 (1H, d, J=5Hz), 7.06 (1H, br, s), 7.27 (1H, br, s), 7.3–7.5 (3H, m), 7.74 (1H, s),7.80 (1H, s)

INDUSTRIAL APPLICABILITY

Novel imidazole compounds having pharmaceutical activity such as ADAinhibiting activity are provided. These compounds are useful inimmunomodulation, especially immunosuppression, antiinflammation andtreatment and prevention of various diseases for which Ado is effective.Such diseases include autoimmune diseases, inflammation, organ or tissueallo- or xeno-transplant rejection, leukemias, and diseases that arisefrom, or are aggravated by, insufficient blood flow through a particularorgan or portion thereof. These compounds or their prodrugs or salts canbe administered to patients in need of the treatment in an effectiveamount to elevate adenosine concentration.

1. A compound of the formula

wherein R¹ is aryl or heterocyclic group which is optionally substitutedwith substituent(s); R² is lower alkyl; R³ is hydroxy or protectedhydroxy; —A— is lower alkylene; and —X— is —O— or —S—; provided thatwhen —X— is —O—, then R¹ is aryl which is substituted withsubstituent(s), or heterocyclic group which is optionally substitutedwith substituent(s), or a salt thereof.
 2. The compound according toclaim 1, wherein R¹ is (1) aryl optionally substituted withsubstituent(s) selected from the group consisting of lower alkyl,halogen, optionally substituted aryl, optionally substitutedheterocyclic group, lower alkoxy, and cyano, (2) condensed heterocyclicgroup optionally substituted with substituent(s) selected from the groupconsisting of lower alkyl, optionally substituted aryl, andaryl(lower)alkyl, or (3) unsaturated heteromonocyclic group containing 1to 4 nitrogen atoms which is optionally substituted with optionallysubstituted aryl.
 3. The compound according to claim 2, wherein thesubstituent(s) of optionally substituted aryl and optionally substitutedheterocyclic group are selected from the group consisting of loweralkyl, halo(lower)alkyl, lower alkoxy, halogen, aryl, aryl(lower)alkyl,and cyano.
 4. The compound according to claim 1, wherein -A- ismethylene or ethylene.
 5. The compound according to claim 1, wherein R²is methyl.
 6. The compound according to claim 1, which is a compoundselected from the group consisting of: (1)1-[(2S,3R)-2-benzyloxy-5-(6-quinolyloxy)-3-pentyl]imidazole-4-carboxamide;(2)1-[(2S,3R)-2-hydroxy-5-(6-quinolyloxy)-3-pentyl]imidazole-4-carboxamide;(3)1-[(2S,3R)-2-benzyloxy-5-(3,4-dichlorophenoxy)-3-pentyl]imidazole-4-carboxamide;(4)1-[(2S,3R)-5-(3,4-dichlorophenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(5)1-[(2S,3R)-2-benzyloxy-5-(2-dibenzofuranyloxy)-3-pentyl]imidazole-4-carboxamide;(6)1-[(2S,3R)-5-(2-dibenzofuranyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(7)1-[(2S,3R)-2-benzyloxy-5-(2-methyl-5-benzothiazolyloxy)-3-pentyl]imidazole-4-carboxamide;(8)1-[(2S,3R)-2-hydroxy-5-(2-methyl-5-benzothiazolyloxy)-3-pentyl]imidazole-4-carboxamide;(9)1-[(2S,3R)-2-benzyloxy-5-(2-fluorenyloxy)-3-pentyl]imidazole-4-carboxamide;(10)1-[(2S,3R)-5-(2-fluorenyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(11)1-[(2S,3R)-2-benzyloxy-5-(2,3-dichlorophenoxy)-3-pentyl]imidazole-4-carboxamide;(12)1-[(2S,3R)-5-(2.3-dichlorophenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(13)1-[(2S,3R)-2-benzyloxy-5-(7-isoquinolyloxy)-3-pentyl]imidazole-4-carboxamide;(14)1-[(2S,3R)-2-hydroxy-5-(7-isoquinolyloxy)-3-pentyl]imidazole-4-carboxamide;(15)1-[(2S,3R)-5-(6-bromo-2-naphthyloxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide;(16)1-[(2S,3R)-5-(6-bromo-2-naphthyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(17)1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(3,4-dimethylphenoxy)-3-pentyl]imidazole-4-carboxamide;(18)1-[(2S,3R)-5-(3,4-dimethylphenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(19)1-[(2S,3R)-5-(1,1′-biphenyl-3-yloxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide(19); (20)1-[(2S,3R)-5-(1,1′-biphenyl-3-yloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(21)1-[(2S,3R)-5-(1,1′-biphenyl-2-yloxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide;(22)1-[(2S,3R)-5-(1,1′-biphenyl-2-yloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(23)1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(3-isoquinolyloxy)-3-pentyl]imidazole-4-carboxamide;(24)1-[(2S,3R)-2-hydroxy-5-(3-isoquinolyloxy)-3-pentyl]imidazole-4-carboxamide;(25)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[1-methyl-2-(2-phenylethyl)-1H-indol-5-yloxy]-3-pentyl}imidazole-4-carboxamide;(26)1-{(2S,3R)-2-hydroxy-5-[1-methyl-2-(2-phenylethyl)-1H-indol-5-yloxy]-3-pentyl}imidazole-4-carboxamide;(27)1-[(2S,3R)-5-(1,1′-biphenyl-4-yloxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide;(28)1-[(2S,3R)-5-(1,1′-biphenyl-4-yloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(29)1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(3-tert-butylphenoxy)-3-pentyl]imidazole-4-carboxamide;(30)1-[(2S,3R)-5-(3-tert-butylphenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(31)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(32) 1-{(2S,3R)-2-hydroxy-5-[3-(2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide; (33)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[2-(2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(34)1-{(2S,3R)-2-hydroxy-5-[2-(2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(35)1-{(2S,3R)-5-[3-(2-benzylthiazol-4-yl)phenoxy]-2-(tert-butyldimethylsilyloxy)-3-pentyl}imidazole-4-carboxamide;(36)1-{(2S,3R)-5-[3-(2-benzylthiazol-4-yl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(37)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(2-phenylthiazol-4-yl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(38)1-{(2S,3R)-2-hydroxy-5-[3-(2-phenylthiazol-4-yl)phenoxy]3-pentyl}imidazole-4-carboxamide;(39)1-[(2S,3R)-5-(3-bromophenoxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide;(40)1-[(2S,3R)-5-(3-bromophenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(41)1-{(2S,3R)-5-[3-(2-benzo[b]thiophenyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(42)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(4-morpholinyl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(43)1-{(2S,3R)-2-hydroxy-5-[3-(4-morpholinyl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(44)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(5-chloro-2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(45) 1-{(2S,3R)-5-[3-(5-chloro-2-thienyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(46)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(5-methyl-2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(47)1-{(2S,3R)-2-hydroxy-5-[3-(5-methyl-2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(48)1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(2-quinolyloxy)-3-pentyl]imidazole-4-carboxamide;(49)1-[(2S,3R)-2-hydroxy-5-(2-quinolyloxy)-3-pentyl]imidazole-4-carboxamide;(50)1-{(2S,3R)-5-[3-(2-benzoxazolyl)phenoxy]-2-(tert-butyldimethylsilyloxy)-3-pentyl}imidazole-4-carboxamide;(51)1-{(2S,3R)-5-[3-(2-benzoxazolyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(52)1-{(2S,3R)-5-[3-(2-benzofuranyl)phenoxy]-2-(tert-butyldimethylsilyloxy)-3-pentyl}imidazole-4-carboxamide;(53) 1-{(2S,3R)-5-[3-(2-benzofuranyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(54)1-{2S,3R}-5-[3-(1H-benzimidazol-2-yl)phenoxy]-2-(tert-butyldimethylsilyloxy)-3-pentyl}imidazole-4-carboxamide;(55) 1-{(2S,3R)-5-[3-(1H-benzimidazol-2-yl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(56)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(4′-chloro-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(57)1-{(2S,3R)-5-[(4′-chloro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(58)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(3′-chloro-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(59)1-{(2S,3R)-5-[(3′-chloro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(60)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(2′-chloro-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(61)1-{(2S,3R)-5-[(2′-chloro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(62)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(4′-methoxy-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(63)1-{(2S,3R)-2-hydroxy-5-[(4′-methoxy-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(64)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(3′-methoxy-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(65)1-{(2S,3R)-2-hydroxy-5-[(3′-methoxy-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(66)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(2-methoxy-5-pyridyl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(67)1-{(2S,3R)-2-hydroxy-5-[3-(6-methoxy-3-pyridyl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(68)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(6-phenyl-2-pyridyl)oxy]-3-pentyl}imidazole-4-carboxamide;(69)1-{(2S,3R)-2-hydroxy-5-[(6-phenyl-2-pyridyl)oxy]-3-pentyl}imidazole-4-carboxamide;(70)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(4′-fluoro-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(71)1-{(2S,3R)-5-[(4′-fluoro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(72)1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-{[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]oxy}-3-pentyl]imidazole-4-carboxamide;(73)1-[(2S,3R)-2-hydroxy-5-{[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]oxy}-3-pentyl]imidazole-4-carboxamide;(74)1-{(2S,3R)-2-hydroxy-5-[3-(1H-pyrrol-1-yl)-2-naphthyloxy]-3-pentyl}imidazole-4-carboxamide;(75)1-[(2S,3R)-2-hydroxy-5-(1-methyl-1H-indol-5-yl)oxy-3-pentyl]imidazole-4-carboxamide;(76)1-[(2S,3R)-2-hydroxy-5-(2-naphthylthio)-3-pentyl]imidazole-4-carboxamide;(77)1-[(2S,3R)-2-hydroxy-5-(1-naphthylthio)-3-pentyl]imidazole-4-carboxamide;(78)1-[(2S,3R)-2-hydroxy-5-(2-quinolylthio)-3-pentyl]imidazole-4-carboxamide;(79)1-[(2S,3R)-5-(3,4-dichlorophenylthio)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(80)1-[(2S,3R)-5-(3,4-dimethylphenylthio)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(81)1-{(1R,2S)-1-[(3,4-dichlorophenoxy)methyl]-2-hydroxypropyl}-1H-imidazole-4-carboxamide;(82)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(4′-cyano-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide; (83)1-{(2S,3R)-5-[(4′-cyano-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(84)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(4′-methyl-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(85)1-{(2S,3R)-2-hydroxy-5-[(4′-methyl-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(86)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(6-chloro-3-pyridyl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(87)1-{(2S,3R)-5-[3-(6-chloro-3-pyridyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(88)1-((2S,3R)-2-(tert-butyldimethylsilyloxy)-5-{[6-(4-chlorophenyl)-2-pyridyl]oxy}-3-pentyl)imidazole-4-carboxamide;(89)1-((2S,3R)-2-hydroxy-5-{[6-(4-chlorophenyl)-2-pyridyl]oxy}-3-pentyl)imidazole-4-carboxamide;(90)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(3′,5′-dichloro-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(91)1-{(2S,3R)-5-[(3′,5′-dichloro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(92)1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(7-methoxy-2-naphthyloxy)-3-pentyl]imidazole-4-carboxamide;(93)1-[(2S,3R)-2-hydroxy-5-(7-methoxy-2-naphthyloxy)-3-pentyl]imidazole-4-carboxamide;(94)1-[(2S,3R)-5-(7-bromo-2-naphthyloxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide;(95)1-[(2S,3R)-5-(7-bromo-2-naphthyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(96)1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(7-chloro-2-naphthyloxy)-3-pentyl]imidazole-4-carboxamide;(97)1-[(2S,3R)-5-(7-chloro-2-naphthyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(98)1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(7-cyano-2-naphthyloxy)-3-pentyl]imidazole-4-carboxamide;(99)1-[(2S,3R)-5-(7-cyano-2-naphthyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(100)1-((2S,3R)-2-(tert-butyldimethylsilyloxy)-5-{[2-(4-chlorophenyl)-1,3-benzoxazol-6-yl]oxy}-3-pentyl)imidazole-4-carboxamide;(101)1-((2S,3R)-5-{[2-(4-chlorophenyl)-1,3-benzoxazol-6-yl]oxy}-2-hydroxy-3-pentyl)imidazole-4-carboxamide;(102)1-{(1R,2S)-2-hydroxy-1-[(2-naphthylthio)methyl]propyl}-1H-imidazole-4-carboxamide;(103)1-{(1R,2S)-2-hydroxy-1-[(1-naphthylthio)methyl]propyl}-1H-imidazole-4-carboxamidehydrochloride; and (104)1-{(1R,2S)-1-{[(2,3-dichlorophenyl)thio]methyl}-2-hydroxypropyl}-1H-imidazole-4-carboxamide.7. The compound according to claim 1, which is a compound selected fromthe group consisting of: (20)1-[(2S,3R)-5-(1,1′-biphenyl-3-yloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(41)1-{(2S,3R)-5-[3-(2-benzo[b]thiophenyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(53)1-{(2S,3R)-5-[3-(2-benzofuranyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(57)1-{(2S,3R)-5-[(4′-chloro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(59)1-{(2S,3R)-5-[(3′-chloro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(63)1-{(2S,3R)-2-hydroxy-5-[(4′-methoxy-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(85)1-{(2S,3R)-2-hydroxy-5-[(4′-methyl-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(89)1-((2S,3R)-2-hydroxy-5-{[6-(4-chlorophenyl)-2-pyridyl]oxy}-3-pentyl)imidazole-4-carboxamide;(91)1-{(2S,3R)-5-[(3′,5′-dichloro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(95)1-[(2S,3R)-5-(7-bromo-2-naphthyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;and (97)1-[(2S,3R)-5-(7-chloro-2-naphthyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide.8. A pharmaceutical composition comprising the compound of claim 1 as anactive ingredient and a pharmaceutically acceptable, substantiallynon-toxic carrier or excipient.
 9. A pharmaceutical composition havingan adenosine deaminase inhibiting activity, which comprises the compoundof claim 1 as an active ingredient and a pharmaceutically acceptable,substantially non-toxic carrier or excipient.
 10. A method for treating,inflammatory conditions, which comprises administering the compoundwherein the inflammatory condition is selected from the group consistingof rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, goutyarthritis, sunburn, eczema, conjunctivitis, asthma, and bronchitiscompound of claim 1 to a mammal in need of the compound.
 11. A methodfor preparing a medicament, which comprises: mixing the compound ofclaim 1 as an active ingredient with a pharmaceutically acceptable,substantially non-toxic carrier or excipient.
 12. A process forproducing the compound of claim 1, the process comprising any of thefollowing steps (1) to (3): (1) reacting a compound of formula (II)R¹—OH  (II) wherein R¹ is as defined above, with a compound of formula(III)

wherein R², R³, and -A- are as defined above, and X¹ is hydroxy or aleaving group, provided that R³ is not hydroxy; (2) reacting a compoundof formula (I-1)

wherein R¹, R², and -A- are as defined above, and R′ is hydroxyprotective group, with a deprotecting agent; or (3) reacting a compoundof formula (IV)

wherein R¹, R², R³, -A-, and —X— are as defined above, with aqueousammonia solution.